Transposons and the PIWI pathway: genome defense in gametes and embryos

in Reproduction

Hiding in plain sight within the genome of virtually every eukaryotic organism are large numbers of sequences known as transposable elements (TEs). These sequences often comprise 50% or more of the DNA in many mammals and are transcriptionally constrained by DNA methylation and repressive chromatin marks. Individual TEs, when relieved of these epigenetic constraints, can readily move from one genomic location to another, either directly or through RNA intermediates. Demethylation and removal of repressive histone marks during epigenetic reprogramming stages of gametogenesis and embryogenesis render the genome particularly susceptible to increased TE mobilization, which has significant implications for the fidelity of genome replication and subsequent viability of the progeny. Importantly, however, TEs have functionally integrated themselves into developmental events to the extent that complete suppression precludes normal gamete and embryo development. Consequently, multiple mechanisms have evolved to limit the extent of TE expression and mobilization during reprogramming without completely suppressing it. One of the most important TE repression mechanisms is the PIWI/piRNA pathway, in which 25–32 nucleotide RNA molecules known as piRNAs associate with Argonaute proteins from the PIWI clade to form piRISC complexes. These complexes target and silence TEs post-transcriptionally and through the induction of epigenetic changes at the loci from which they are expressed. This review will briefly discuss the intricate molecular détente between TE expression and its suppression by the PIWI pathway, with particular emphasis on mammalian species including human, bovine and murine.

Abstract

Hiding in plain sight within the genome of virtually every eukaryotic organism are large numbers of sequences known as transposable elements (TEs). These sequences often comprise 50% or more of the DNA in many mammals and are transcriptionally constrained by DNA methylation and repressive chromatin marks. Individual TEs, when relieved of these epigenetic constraints, can readily move from one genomic location to another, either directly or through RNA intermediates. Demethylation and removal of repressive histone marks during epigenetic reprogramming stages of gametogenesis and embryogenesis render the genome particularly susceptible to increased TE mobilization, which has significant implications for the fidelity of genome replication and subsequent viability of the progeny. Importantly, however, TEs have functionally integrated themselves into developmental events to the extent that complete suppression precludes normal gamete and embryo development. Consequently, multiple mechanisms have evolved to limit the extent of TE expression and mobilization during reprogramming without completely suppressing it. One of the most important TE repression mechanisms is the PIWI/piRNA pathway, in which 25–32 nucleotide RNA molecules known as piRNAs associate with Argonaute proteins from the PIWI clade to form piRISC complexes. These complexes target and silence TEs post-transcriptionally and through the induction of epigenetic changes at the loci from which they are expressed. This review will briefly discuss the intricate molecular détente between TE expression and its suppression by the PIWI pathway, with particular emphasis on mammalian species including human, bovine and murine.

Genomic assailants from within: transposable elements

The trans-generational propagation of genes from parent to offspring is an indispensable component of the process of reproduction. Faithful genome replication is threatened in eukaryotic organisms by viral elements that have the potential to cause mutations and compromise the fitness of subsequent generations or damage the genome such that reproduction is no longer possible. Surprisingly perhaps, the richest source of these viral elements lies within an organism’s own DNA in the form of integrated sequences known as transposable elements (TEs) that are often virus derived.

TEs are mobile DNA sequences present within the eukaryotic genome (Fedoroff 2012). They were discovered in plants by Barbara McClintock where they were observed to move within and between chromosomes and subsequently named ‘jumping genes’ (McClintock 1950). In higher eukaryotes, these sequences constitute a significant fraction of the genome; approximately 50% of human and bovine genomes are composed of TEs and their derivatives (Lander et al. 2001). While a large number of these elements are evolutionarily conserved, more than one quarter appear to be species specific (Adelson et al. 2009). Most TEs are fragmented and cannot undergo independent transposition, but some remain intact and competent to mobilize within the genome. The frequency of activation is reflected in the observation that approximately 10% of all spontaneous genome mutations in rodents appear to result from TE mobilization (Kazazian 1998). Surprisingly perhaps, mechanisms to completely eliminate or permanently suppress transposons within the genome have not evolved, raising important questions with respect to the high potential fitness costs of continually replicating large amounts of DNA with no obvious coding or regulatory functions. In particular, the possibility must be considered that TEs provide unrecognized advantages to host genomes.

Transposable elements are categorized in two classes and a number of subclasses based on the mechanism of transposition. Class I elements, also known as retrotransposons, (Wicker et al. 2007, 2008) move through RNA intermediates that are transcribed in a manner similar to coding genes. Intact retrotransposons can mobilize through transcription then re-integrate into the genome through the activities of reverse transcriptase (RT) and endonuclease enzymes that are encoded by the TE (Wicker et al. 2007). Common examples of this class are long terminal repeat (LTR)/endogenous retroviruses (ERV) and non-LTR retrotransposons, including the long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs) (Fig. 1A).

Figure 1
Figure 1

Structure and activty of common mammalian transposable elements (TEs). Note: Due to the generally dispensable nature of most TEs, there are many permutations of the structures described here. (A) Long and short interspersed nuclear elements (LINEs and SINEs) are flanked by target site duplications due to the mechanism of LINE1 retrotransposition. Transcription of LINE1 is initiated after association of RNA polymerase (RNA pol) II with the TE promoter sequence (black bent arrow) in the 5′ UTR. Complete copies encode two open reading frames (ORF1 and ORF2), followed by the 3′ UTR and poly(A) tail. Both ORF1 and ORF2 are required for LINE1 retrotransposition; the former encoding a nucleic acid chaperone and the latter a protein with endonuclease (EN) and reverse transcriptase (RT) domains. SINEs are dependent on LINE1 ORF2 for retrotransposition, and do not encode proteins. Their structures are highly variable, but two conserved primate elements are presented here: Alu and SVA. Alu is transcribed by RNA pol III from a promoter (gray bent arrow) in the left monomer, which terminates downstream of the element at the closest genomic terminator sequence (poly(T)). Alu contains two monomers that form independent secondary RNA structures, an A-rich spacer (An), and a poly(A) tail. A full length SVA is a ‘repeat of repeats’, composed of a CCCTCT repeat, an Alu-like domain, a GC-rich variable number of tandem repeats, and SINE-R derived from the HERV-K LTR element, followed by a poly(A) tail. It is transcribed by both RNA pol II and pol III at either internal or external promoters, and terminates similar to Alu. Finally, ERVs are transcribed by RNA pol II and encode 2–3 proteins: gag (viral core protein), pol (RT, integrase, protease) and sometimes env (viral envelope protein). ERVs are flanked by long terminal repeats (LTRs), a hallmark of their mechanism of retrotransposition. (B) Prior to reprogramming or specific cell stress, TEs are packaged into heterochromatin and their activity is suppressed, primarily through repressive DNA and histone methylation. During reprogramming, repressive marks are removed and TEs may be transcribed. A complete LINE1 element contains two coding domains, which produce ORF1 and ORF2, forming a ribonucleoprotein complex with LINE1 transcripts. Upon translocation to the nucleus, ORF2 creates a single-stranded nick in the DNA, which allows target primed reverse transcription of a new complete or partial (depicted here), LINE1 element in the genome. In contrast, SINEs only require ORF2 to replicate. Adapted from (Ostertag et al. 2003, Beck et al. 2011, Deininger 2011).

Citation: Reproduction 156, 4; 10.1530/REP-18-0218

Within the LINE retrotransposons, LINE1 (L1) is an autonomous element (encoding the proteins required for retrotransposition) normally consisting of a few thousand base pairs (bp) (Swergold 1990). It is transcribed similarly to genic mRNA, utilizing RNA Polymerase II (Pol II) followed by 5′ capping and polyadenylation . Two open reading frames (ORFs) are present in a complete L1 transcript; ORF1 encodes an RNA-binding protein and ORF2 encodes a protein with RT and endonuclease activities (Ostertag & Kazazian 2001, Martin 2006). Together, ORF1 and ORF2 facilitate L1 RNA translocation to the nucleus, reverse transcription and reintegration into DNA (Ostertag & Kazazian 2001) (Fig. 1B). The L1 element has been described as the only autonomous non-LTR retrotransposon in mammals, with the exception of marsupials and ruminants which have LINE RTE repeats in addition to LINE1 (Deininger et al. 2003). The bovine genome encodes nine complete copies of the LINE RTE BovB, which includes a reverse transcriptase similar to L1 (Adelson et al. 2009) suggesting that the L1 class of retrotransposons may be active in this species.

In contrast to LINEs, SINEs are non-autonomous and transcribed by Pol III (Kroutter et al. 2009). SINEs (and some fragmented LINEs) capitalize on the L1 retrotransposition machinery, specifically requiring ORF2 from L1 for successful retrotransposition (Kroutter et al. 2009). There is greater variation in SINE classes between species, with bovine SINEs dominated by BOV-A2, Bov-tA and tRNA insertions (Adelson et al. 2009) and human by Alu and SVA type SINEs (Ostertag et al. 2003, An et al. 2004). SINE elements range from 85 to 500 base pairs and contain an internal Pol III promoter (Deininger 2002). However, the majority of both LINEs and SINEs in mammalian genomes have lost their functional promoters (Deininger 2002).

Endogenous retroviruses (ERVs) are less abundant in the bovine genome, at between 0.4 and 4.3% of total DNA and approximately 13,000 copies, depending on the detection algorithm applied (Garcia-Etxebarria & Jugo 2010). Structurally, ERVs encode the canonical retroviral GAG, POL and ENV proteins over 5–10 kilobases (kb), flanked by LTRs of between 300 and 1200 bps. The gag gene encodes the core viral proteins that bind the retroviral RNA genome, the pol region encodes the RT and integrase responsible for genomic reintegration and the env region encodes surface and transmembrane proteins that facilitate receptor binding and membrane fusion (Ryan 2004). Importantly, ERVs show considerable variability in sequence due to the accumulation of mutations, insertions and deletions (Stoye 2012). Moreover, recombination events involving LTRs of ERVs can lead to excision of the coding regions, leaving behind ‘Solo LTRs’ that are much more abundant than full or partial ERVs (Benachenhou et al. 2009). Recent studies by Svoboda and colleagues (Franke et al. 2017) have demonstrated that LTRs have strong potential to play important roles in gene evolution and expression control in oocytes and early embryos of many different species including bovine.

The second major class of TEs consists of Class II elements, also called DNA-transposons, which replicate through a DNA intermediate, by rolling circle replication or through other unknown mechanisms (Wicker et al. 2007). Class II TEs comprise only about 2% of the bovine genome and will not be discussed further here. For a recent discussion of DNA TEs in mammals (see Hickman & Dyda (2015)).

Transposable element expression

The expression of TEs is normally suppressed epigenetically by methylation of cytosine and guanine residues in DNA and repressive marks on histones (Huda et al. 2010, Zamudio et al. 2015). However, as described in more detail below, TEs become transcribed at higher frequency during periods of genome demethylation, increasing the probability of transposition events. In principle, transposition leads to one of three outcomes: positive, negative or neutral effect on host viability. The net effect depends on the integration site and downstream impacts of the new TE on the expression or function of nearby genes. TEs have contributed substantially to the evolution of the bovine genome in which an average of 18 TE insertions per gene (in regulatory and coding regions) have been identified (Almeida et al. 2007). While no formal associations between TEs and heritable diseases in cattle are apparent in the literature, many examples of diseases resulting from retrotransposition are present in humans (Kazazian et al. 1988). TE mobilization is also observed in different human cancers, but whether TE expression is the cause, or a consequence, of genomic instability is not clear (reviewed in Belancio et al. 2010). Mechanistically, disease-causing TE insertions typically disrupt the coding sequence or processing (i.e. splicing) of mRNAs (Maksakova et al. 2006). As with any mutation, TE insertion would be predicted to cause more negative than positive effects on the host cell, and therefore, most cells or progeny in which retrotransposition occur are likely subject to negative selection.

TE expression in embryos

Despite the deleterious potential of TE expression and reintegration, specific TEs and their truncated transcripts appears to be beneficial, or at least required, during embryogenesis where they are frequently expressed (Beraldi et al. 2006). In support of a functional requirement for specific TE expression, suppression of the L1 ORF1 in murine zygotes increases the rate of embryo arrest (Beraldi et al. 2006). A recent investigation by Jachowicz et al. demonstrated that not only is LINE1 expression required for early mouse embryogenesis, but that it must be subsequently silenced for successful progression to the blastocyst stage (Jachowicz et al. 2017). Furthermore knockdown of MuERV-L, one of the first transcripts generated from the quiescent mouse genome after fertilization, leads to a developmental block at the four-cell stage (Kigami et al. 2003). Moreover, ample evidence suggests that specific TE transcripts are actively regulated throughout development in many species (Ge 2017).

Evolutionary selection for TE expression may have resulted from the tendency of these elements to contain regulatory domains that are frequently co-opted by genes near the insertion sites (Töhönen et al. 2015, Franke et al. 2017). The regulatory mechanisms in which they participate can be particularly complex, making them difficult to fully elucidate (Sokol et al. 2015). The contribution of TEs to gene regulation in mouse and human genomes has been investigated at the genome level (Faulkner et al. 2009). TEs situated upstream of 5′ untranslated regions (UTRs) tend to function as enhancers or alternate promoters (Bejerano et al. 2006, Franke et al. 2017). The promoters for L1 and LINE-like elements are internal to the transcription start site, which prevents promoter loss and provides potential alternative start sites for genes into which they transpose (Swergold 1990). In addition, a large fraction of Refseq genes (~25%) contain one or more TE insertions in their 3′ UTRs (Faulkner et al. 2009). Globally, these transcripts show decreased expression as TE coverage in their 3′ UTRs increases, suggesting that negative regulatory functions can often be ascribed to repeat sequences in this region. In support of this, SINE Alu elements contain a poly(T) sequence that contributes approximately 40% of the sequence present in known 3′UTR AU-rich elements (ARE) (An et al. 2004). AREs are critical for mRNA stability and regulation through binding of proteins that facilitate or impair mRNA degradation (reviewed in Barreau et al. 2005). In addition to altering the regulatory regions of existing genes, TEs participate in the generation of retrogenes – host mRNAs that have undergone reverse transcription, with the resultant cDNAs incorporated into the genome as intron-less genes (Buzdin et al. 2003). Recent work by Hendrickson et al. (2017) demonstrates that the retrogene paralogs DUX/DUX4 are indispensable for embryo cleavage in mice and humans, highlighting a particularly relevant example of this process in embryos. In a fascinating twist on this observation, transcripts induced by the DUX retrogene product (a transcription factor) include the endogenous retroviruses M/HERVL, directly suggesting an explanation for the persistence of this TE in the genome. Finally, expression of the maternally inherited factor Stella in oocytes is required for embryo progression past the 4-cell stage (Payer et al. 2003). Recently, Stella has been shown to induce the expression of ERVs during the maternal-to-zygotic transition (MZT), which appears to be critical for mouse embryo development (Huang et al. 2017), reinforcing the importance of regulated TE expression during development.

The advantages of TE expression

Increased awareness that TEs may confer fitness advantages to their hosts has contributed to a significant shift in the perception of their roles and importance. While previously considered parasitic ‘passengers’ in the genome that were occasionally responsible for disease, TEs are now more commonly considered ‘evolutionary drivers’ and ‘exaptation mediators’ that exist symbiotically in the genome (Elbarbary et al. 2016).

In addition to their roles in altering the landscape of regulatory regions in coding genes, a number of studies have demonstrated that TE expression is increased in response to stress. This association is most firmly established in plants, where tissue damage, pathogen exposure or heat stress increases TE expression (reviewed in Wessler 1996, Capy et al. 2000). In yeast, Ty retrotransposon expression is increased after ethanol exposure (Stanley et al. 2010). TE expression changes in response to stress are not as widely documented in mammals. Interestingly, higher numbers of Alu elements are present in the regulatory elements of genes involved in stress and immune responses (van de Lagemaat et al. 2003), suggesting that common regulatory elements may control their expression. Furthermore, SINE-mediated mRNA regulation has been observed in mammals under stressful conditions (reviewed in Elbarbary et al. 2016). In addition to stress, hormonal stimuli can drive TE activation, HERV expression in human breast cancer cells and LTR VL30 expression in mouse reproductive organs are increased in response to steroid hormones (Ono et al. 1987, Schiff et al. 1991). Based on these observations, it is reasonable to speculate that TE expression also depends on environmental stimuli in the context of early mammalian development. Regardless of where TEs transpose within the genome or the stimuli that cause them to do so, selection for the accumulated beneficial changes they induce has clearly contributed to their persistence.

TE mobilization during reprogramming

While emerging evidence suggests that regulated TE expression is associated with normal embryogenesis, unregulated, widespread expression and reintegration of mobile elements during reprogramming poses significant risks to the genome. Reprogramming refers to the erasure and re-writing of specific epigenetic marks, namely DNA methylation and histone modifications. In the context of reproduction, reprogramming occurs twice: once during gametogenesis and again during early embryogenesis (Morgan et al. 2005). The resultant chromatin state leads to TE de-repression (reviewed in Leung & Lorincz 2012). Human embryos express TEs from various classes including L1, Alu, SVA and HERV-K (Adjaye et al. 1997, Guo et al. 2014, Grow et al. 2015). HERV-K transcription is driven by OCT4 and produces functional proteins that are present in the blastocyst and capable of RNA binding, although their developmental roles are unknown (Grow et al. 2015).

Two published studies have investigated the expression of TEs during bovine reprogramming. In both in vitro-produced (IVP) and -cloned (SCNT) embryos, marked induction of three ERVs was observed in one study (Bui et al. 2009). A 1000-fold increase in ERV1_1_BT was seen between the four-cell and morula stages for both the IVP and SCNT groups. Independently, seven TE families were examined between the four-cell and blastocyst stages (Li et al. 2016). Low or highly variable expression was observed in four of the seven families, and L1, BovB and ERV1_1_BT showed increased expression from the four-cell to blastocyst stages, with ERV1_1_BT showing a similar increase to that seen in the Bui study. These findings highlight marked changes in TE expression in the bovine embryo during the MZT.

Some inference regarding TE activity can be obtained from evaluating the overall abundance of specific TEs in the genome; L1 BT and BovB comprise 11 and 10% of the bovine genome respectively (Adelson et al. 2009). Seventy-three potentially active copies of L1 BT and nine of BovB are present. The SINE element Bov-tA is substantially more abundant, with approximately 1.5 million copies. Based on these data, the L1 BT family of TEs is likely the most active, along with SINE elements that exploit the L1 ORF genes in their replication/reintegration cycles. In the endogenous retrovirus (ERV) category, 24 families and ~13,622 total ERV elements are present (Garcia-Etxebarria & Jugo 2010) suggesting substantial recent activity in evolutionary terms.

Studies on TEs during reprogramming in gametes have focused primarily on the mechanisms responsible for TE suppression, particularly in the mouse, where knockout of several different repressive pathways arrests meiosis through genomic instability in both sexes (Aravin et al. 2007a, Carmell et al. 2007, Kuramochi-Miyagawa et al. 2008, Flemr et al. 2013). In particular, widespread activation of the L1 and ERV families during spermatogenesis is observed when repressive mechanisms are inhibited (Aravin et al. 2007a, Flemr et al. 2013). Activation of TE transcription and its consequences during oogenesis is less extensively studied, although recent studies employing oocyte-specific deletion of the histone methyltransferase Setdb1 highlight the need for some level of epigenetic suppression of TE expression (Eymery et al. 2016). In one example of the requirement for TE activation, LINE1 ORF1 protein is required for exit from meiotic arrest in mouse oocytes, while overexpression inhibits progression to metaphase II (Luo et al. 2016). ORF1 is also expressed at variable levels in fetal oocytes, with overexpression leading to meiotic prophase I defects (Malki et al. 2014). Studies on the murine LTR TE mouse transcript (MT) expressed in neonatal to mature oocytes (Park et al. 2004, Holt et al. 2006) suggest that it accounts for 10% of total oocyte transcripts (Peaston et al. 2004) although no function is recognized. In support of its importance, RNAi-mediated inhibition of MT expression in GV oocytes inhibited germinal vesicle breakdown (GVBD), implicating MT in oocyte maturation (Peaston et al. 2004). Overall, TE regulation appears important to ensure that some level of TE expression occurs during the reprogramming stage of gametogenesis without excessive activation. The functions of TE expression in this context and the evolutionary forces that drive their selection are not known.

Control of TE expression during reprogramming

Given the delicate balance between the positive effects of limited TE expression during reprogramming, and the severe genomic damage that results from TE overexpression, it is perhaps not surprising that a number of distinct pathways have evolved to control their expression. Endogenous siRNAs appear to be particularly important in mouse oocytes, where suppression of Dicer or Ago2 increases the levels of MT transcripts and abnormalities in spindle formation during meiosis I (Watanabe et al. 2008, Stein et al. 2015). This pathway may be most important in the mouse and rat, which have acquired a unique oocyte-specific variant of Dicer (Dicero) (Flemr et al. 2013). However, recent studies on L1 targeting endo-siRNAs in the pig suggest that Dicer and Ago2 are also important in other species (Zhang et al. 2017). Small RNA pathways in which targeting RNAs derived from tRNAs (known as tRFs) have recently been shown to suppress LTR TEs in mice (Schorn et al. 2017). In this pathway, 18 nt tRFs selectively antagonize RT action (an obligate step in replication for this TE class) while 22nt tRFs act as endo-siRNAs, participating in RISC-dependent destruction of TE transcripts. Additional pathways involving the proteins MARF1 (Su et al. 2012), Stella (Huang et al. 2017), RIF-1 (Li et al. 2017) and TRIM28 (Tao et al. 2018) are also important in TE repression and act through epigenetic and transcriptional modulation, but lie beyond the scope of this review. The most widely studied pathway involved in the control of TE expression is the PIWI/piRNA pathway.

PIWI proteins and piRNAs – permissive, targeted TE defense

A clade of Argonaute family members known as PIWI proteins and their associated small (25–32 nt) RNAs form the central components of a genome protection mechanism known as the PIWI/piRNA pathway (Aravin et al. 2006, Saito et al. 2006, Vagin et al. 2006, Brennecke et al. 2007). The pathway was originally described in Drosophila gametes where its role in limiting TE expression was first recognized (Lin & Spradling 1997, Aravin et al. 2001, Deng & Lin 2002, Vagin et al. 2006). The name is derived from the phenotype ‘P-element Induced WImpy testis’ (PIWI), where a mutation in the PIWI gene of Drosophila was induced by a Class II transposon (P-element) to which some strains are particularly susceptible (Lin & Spradling 1997). The importance in reproduction was immediately evident as both male and female progeny are sterile (Lin & Spradling 1997). The first identified mechanism of action involved the interaction of PIWI proteins with piRNAs of specific sequences complementary to RNA targets (i.e. expressed TEs) to form a piRNA-induced silencing complex (piRISC) that specifically cleaves the RNA target through RNase activity of the complex (Aravin et al. 2006, Girard et al. 2006, Gunawardane et al. 2007). Additional potential roles in targeting mRNA transcripts have recently been reported in germline and somatic cells (Rajasethupathy et al. 2012, Chen et al. 2013, Kwon et al. 2014, Nandi et al. 2016, Russell et al. 2017), although the extent and importance of this targeting is not yet clear. This review will focus primarily on the established roles of PIWI proteins and their associated piRNAs in the control of TE expression.

A systematic examination of mutations that impacted germline stem cell viability led to the identification of the first PIWI gene in Drosophila (Lin & Spradling 1997) where PIWI gene mutations result in cellular loss (Cox et al. 1998). The Drosophila PIWI proteins, Argonaute3 (Ago3) and Aubergine (Aub), were subsequently characterized based on their structural similarity and co-localization with PIWI in the pole plasm (Wilson et al. 1996, Harris & Macdonald 2001, Williams & Rubin 2002). Structurally all proteins of the PIWI family contain a PIWI domain, which has RNase activity, in addition to N-terminal, PIWI/Argonaute/Zwille and MID domains (Cora et al. 2014). The importance of the PIWI pathway in mammalian reproduction was first demonstrated in the mouse, where the PIWI homolog MIWI (PIWI-like 1 or PIWIL1) was shown to be essential for spermatogenesis (Deng & Lin 2002). Mouse PIWIL1 is expressed during spermatogenesis between the pachytene stage and the round spermatid stage where it silences TEs and specific mRNAs (Reuter et al. 2011, Gou et al. 2014). A similar expression pattern is observed in the bull (Russell et al. 2016) and dog (Stalker et al. 2016). The key mechanism of PIWI action was identified when it was shown to bind a class of small RNAs that guide complementary interactions with target RNA transcripts including TEs (Aravin et al. 2006, Girard et al. 2006, Lau et al. 2006, Brennecke et al. 2007, Carmell et al. 2007).

Two additional murine PIWI homologs were identified in subsequent studies: MILI (PIWIL2) and MIWI2 (PIWIL4) (Aravin et al. 2006, Carmell et al. 2007). PIWIL2 is thought to be the oldest PIWI protein in evolutionary terms (Kuramochi-Miyagawa et al. 2008) and has the most extensive period of expression throughout spermatogenesis, starting at the primordial germ cell stage in utero and persisting to the pachytene stage (Kuramochi-Miyagawa et al. 2004, Aravin et al. 2006). Mice lacking PIWIL2 develop genomic instability and elevated TE expression after which spermatogenesis becomes blocked in prophase of meiosis I (Kuramochi-Miyagawa et al. 2004, Reuter et al. 2009). PIWIL2 is localized to the cytoplasm, primarily in perinuclear granules, a known site for RNA processing (Aravin et al. 2008). PIWIL4 is found in the pre-natal testis and is expressed from 15.5 days post-coitum until 3 days after birth in prospermatogonia (Aravin et al. 2008) coinciding with an important period of de novo DNA methylation (Lees-Murdock et al. 2003, Maatouk et al. 2006). PIWIL4 distribution is primarily nuclear, with limited expression in cytoplasmic granules (Aravin et al. 2008). One potentially important but less thoroughly studied member of the PIWI clade is PIWIL3, which is encoded in human, bovine (Roovers et al. 2015) and other genomes, but absent in the mouse and rat where most functional studies have been performed. Recent evidence suggests that PIWIL3 expression is normally limited to oocytes and embryos (Roovers et al. 2015, Virant-Klun et al. 2016, S J Russell and J LaMarre, unpublished observations). The roles and importance of this protein are largely unknown.

Regulation of piRNA precursor expression from genomic ‘clusters’

Most mature piRNAs are generated from longer RNA transcripts originating in specific piRNA-rich genomic regions called piRNA clusters (Brennecke et al. 2007). piRNA clusters consist mostly of repetitive element and transposon fragments that have integrated into the genome throughout the course of evolution and which reflect the history of transposition and virus integration into the genome of a species and its evolutionary ancestors (Aravin et al. 2007a). Several hundred to a few thousand clusters are present in the mammalian genomes examined (Lau et al. 2006, Aravin et al. 2007a, Brennecke et al. 2007, Gebert et al. 2015, Russell et al. 2017). The factors that regulate transcription from these clusters (enhancers, epigenetic status) remain poorly characterized. Transcription of piRNA precursor RNAs can occur from a single, or from both strands of DNA, and are respectively classified as uni- or dual-strand clusters (Aravin et al. 2006, Lau et al. 2006, Brennecke et al. 2007, Carmell et al. 2007). Uni- or bi-directional transcription from uni-strand clusters is mediated by RNA polymerase II (Pol II) from one transcription start site, precursors are then polyadenylated, 5′ capped and sometimes subjected to alternative splicing (Goriaux et al. 2014). Expression from dual-strand clusters may be due in part to overlapping, run-through transcription from nearby genes (Mohn et al. 2014). However, recent studies in flies have identified a novel heterochromatin-dependent transcriptional process through which the basal transcription machinery containing a variant of transcription factor II A named ‘Moonshiner’ associates with another protein known as Rhino to license transcription from heterochromatin at piRNA clusters (Andersen et al. 2017).

Two distinct ‘waves’ of piRNA expression occur in murine testes (Vourekas et al. 2012) and the piRNAs from these waves are named based on the timing of their expression. Pre-pachytene piRNAs are present during early spermatogenesis and are primarily targeted at TEs and associate with PIWIL2 and PIWIL4 (Aravin et al. 2008, Li et al. 2013). Pachytene piRNAs are abundantly expressed in pachytene spermatocytes and round spermatids in adult mouse testes and physically associate with PIWIL1 and PIWIL2 (Aravin et al. 2006, Girard et al. 2006). Transcription of pachytene piRNA precursors is driven by the transcription factor A-MYB, which also facilitates PIWIL1 transcription, increasing processing ‘capacity’ for the cluster-derived precursor piRNAs induced at that time (Li et al. 2013). Interestingly, in addition to TEs, pachytene piRNAs may also target mRNAs and have been strongly implicated in the widespread active decay of mRNAs that occurs late in spermatogenesis (Gou et al. 2014). PIWI pathway targeting of mRNAs may not be limited to testes, as piRNAs that appear to target mRNAs have also been recognized in bovine oocytes (Russell et al. 2017).

Export and processing – primary piRNA biogenesis

The generation of piRNAs from primary cluster transcripts is termed primary piRNA biogenesis (Aravin et al. 2007b). After transcription, piRNA transcripts move from the nucleus to the nuage, a peri-nuclear ‘cloud’ containing structures also known as germ granules, Yb bodies, chromatoid bodies, pi-bodies and piP-bodies depending on the cell type and content (Buchan & Parker 2009, Ishizu et al. 2012, Pillai & Chuma 2012, Meikar et al. 2014). The nuage contains mRNA processing machinery and is a known site of decay, storage and quality assessment for RNA (Buchan & Parker 2009, Kulkarni et al. 2010, Meikar et al. 2014). Transcription of piRNA precursors is coupled to the processing machinery in the nuage by the DEAD box helicase UAP56 (Shen 2009, Zhang et al. 2012). Precursors to piRNAs remain single stranded (in contrast to siRNAs and miRNAs) or assume unrecognized structures prior to processing (Houwing et al. 2007). Nucleo-cytoplasmic shuttling is facilitated by the protein Maelstrom (Mael) in Drosophila and mice, which interestingly plays different roles in each species (Aravin et al. 2009, Sienski et al. 2012). In Drosophila, Mael participates in nuclear silencing of transposons in conjunction with PIWI but is not required for piRNA biogenesis (Sienski et al. 2012). In contrast, Mael is required for piRNA biogenesis during pachytene spermatogenesis in mice and binds piRNA precursors that associate with the nuage. Inactivation of Mael results in meiotic arrest and the dissociation of perinuclear granules containing PIWIL4, leading to failure of LINE1 repression (Aravin et al. 2009). These findings implicate Maelstrom in both pre-pachytene PIWIL4 functions and pachytene piRNA biogenesis.

Exported piRNA precursors are processed in several subsequent steps in the nuage, all of which appear closely associated with the mitochondria. An endonuclease known as Zucchini (Zuc; mZuc or mitoPLD in the mouse) processes precursors into intermediate fragments (Pane et al. 2007, Watanabe et al. 2011a, Ipsaro et al. 2012, Nishimasu et al. 2012) after the RNA helicase Armitage (Armi; MOV10L1 in the mouse), unwinds RNA secondary structure (Frost et al. 2010, Vourekas et al. 2015). Physical loading of piRNA intermediates onto PIWI proteins in the nuage requires the co-chaperones shutdown (Shu) and heat shock protein 90 (HSP90) (Olivieri et al. 2012, Izumi et al. 2013).

The next step in piRNA biogenesis is 3′ trimming, which occurs after intermediates are loaded onto PIWI proteins. Mature piRNA length (extent of trimming) appears to depend on the specific PIWI protein to which it is bound – the modal size of mature piRNAs bound to PIWIl1, PIWIL2 and PIWIL4 are 29–30, 26–27, 27–28 nt respectively (Kuramochi-Miyagawa et al. 2008, Vourekas et al. 2012). An enzyme known as Nibbler is a mut-7 homolog in Drosophila which likely mediates the 3′–5′ exonuclease activity (Han et al. 2011, Kawaoka et al. 2011, Wang et al. 2016) for piRNAs bound to PIWI proteins, however the mammalian homolog is unidentified. Nibbler activity depends on TDRKH (also called Papi), which is present at the mitochondrial membrane (Chen et al. 2009, Honda et al. 2013, Saxe et al. 2013). In the final processing step, fully cleaved piRNAs, when bound to PIWI proteins, become 3′-methylated through the activity of Hen1/Pimet, which produces a 2′-O-methyl modification (Horwich et al. 2007, Saito et al. 2007). At the completion of biogenesis, the mature piRNA–PIWI protein complex is considered a ‘piRNA-induced silencing complex’ (piRISC).

The ping-pong amplification loop – generation of secondary piRNAs

One of the most unique elements of the piRNA pathway is a secondary ‘feed-forward’ biogenesis process known as the ‘Ping-Pong’ amplification loop. This loop is considered the secondary piRNA biogenesis pathway (Aravin et al. 2008). In Drosophila, piRNAs generated through primary biogenesis and bound to Aubergine target TEs in the cytoplasm leading to cleavage of the target RNA through RNase slicer activity (Brennecke et al. 2007, Gunawardane et al. 2007). Rather than becoming degraded with the target, the resulting cleaved RNA products load directly onto another PIWI protein, Ago3, as intermediate piRNAs that then become trimmed and 2′-O-Me modified as described above (Han et al. 2015, Wang et al. 2016). These secondary Ago3 piRISC complexes resulting from this ‘ping’ step may then reciprocally target primary piRNA precursors (‘pong’ step) and amplify the number of targeting piRNAs available for silencing through the PIWI pathway (Brennecke et al. 2007). The reciprocal cleavage events, combined with the positional nature of cleavage through this pathway result in a ten nucleotide overlap in piRNA populations that have undergone ping-pong amplification (Aravin et al. 2008). This ping-pong ‘signature’ of overlapping complementary nucleotides is visible as a defined peak when plotted (for examples see Russell et al. 2017).

One important consequence of secondary piRNA generation through the ping-pong cycle is higher sequence diversity in piRISC complexes. Cleavage products from Ago3 in Drosophila when loaded onto PIWI, can direct transcriptional gene silencing (TGS) (Fig. 2; Senti et al. 2015). Similarly, mouse PIWIL2-cleaved targets can associate with PIWIL4, which also direct TGS in the nucleus after translocation (De Fazio et al. 2011). Primary and secondary piRNA biogenesis require a number of cofactors. Anchoring PIWI proteins to the scaffold in the nuage are a family of Tudor domain-containing proteins (TDRDs), TDRD9, TDRD1 and TDRDKH, that bind to symmetric dimethylarginines (sDMAs) on the PIWI proteins (Reuter et al. 2009, Shoji et al. 2009, Saxe et al. 2013). In the Drosophila nuage, the proteins Spindle-E, Krimper, Tejas, Tapas and Qin (Lim & Kai 2007, Malone et al. 2009, Patil & Kai 2010, Zhang et al. 2011) are involved as reviewed extensively elsewhere (Czech & Hannon 2016). In the mouse, a gamete-specific protein known as GTSF1 (Yoshimura et al. 2018) that was previously implicated in other aspects of PIWI/piRNA function (Dönertas et al. 2013, Ohtani et al. 2013) has very recently been shown to be required for secondary piRNA generation. The protein Vasa appears to play an important part in piRNA biogenesis in the silkworm model of the PIWI pathway. Here, piRNA intermediates generated by PIWIL1 bind to Vasa and are protected from degradation, facilitating their transfer to Ago3 (Xiol et al. 2014). Similarly, in mice, the Mouse Vasa Homolog (MVH) participates in retrotransposon suppression during fetal male and female gametogenesis; targeted MVH knockout generates a phenotype remarkably similar to PIWIL2 or PIWIL4 (Kuramochi-Miyagawa et al. 2010, Lim et al. 2013) supporting a conserved role across species.

Figure 2
Figure 2

Mechanisms of regulation by the PIWI pathway. (A) Post-transcriptional gene regulation (PTGS) of transposable elements (TE) or mRNA by piRNA-induced silencing complexes (piRISC). PiRISCs can regulate target RNA by recruiting the CAF1 deadenylation complex or through endonuclease activity and target degradation. (B) Transcriptional gene silencing is mediated by recruitment of DNA methyltransferases or chromatin components to maintain repression of TE loci.

Citation: Reproduction 156, 4; 10.1530/REP-18-0218

An elegant series of recent studies (Han et al. 2015, Mohn et al. 2015) have identified mechanisms by which a subset of piRNAs are ‘phased’ during the biogenesis process, further increasing the variability of targeting piRNAs generated by the pathway. Phased piRNA generation proceeds when PIWI proteins (PIWI in the fly and PIWIL2 in the mouse) are recruited to the 5′ end of precursor transcripts and define a cleavage position 3′ to the complex. The endonuclease Zucchini (MitoPLD in the mouse) is then recruited and cleaves the precursor transcript at this 3′ position, defining the 3′ end of the piRNA and leaving a new 5′ terminus on the precursor, upon which the process repeats. In the mouse the piRNAs generated are further processed by Nibbler in association with TDRKH (Hayashi et al. 2016). The multiple pathways described highlight the complexity of biogenesis and suggest that additional factors, which participate in piRNA biogenesis and TE silencing are likely to be identified as the pathway continues to be characterized.

Mechanisms of piRNA suppression of TEs

Through the generation of piRISC complexes, the PIWI pathway suppresses TE and gene expression through several distinct mechanisms. Complementary RNA targets such as retrotransposon-encoded RNAs are cleaved by RNase slicer activity (Fig. 1A) (reviewed in Hirakata & Siomi 2016). Although less extensively studied, piRISC complexes also help induce epigenetic changes in chromatin conformation and DNA methylation patterns at specific loci in flies (Fig. 1B; Sienski et al. 2012) and mice (Kuramochi-Miyagawa et al. 2008). Cleavage of TE RNA transcripts by piRNA-guided slicer activity of piRISC complexes is the best-studied and first-recognized function of the PIWI pathway (Reuter et al. 2011, Zhang et al. 2015). This post-transcriptional silencing pathway mediated by PIWI proteins participates in both TEs and mRNA cleavage. Targeting and cleavage by piRISC complexes appears more stringent than for some other RISC complexes, requiring a minimum of 16–22 continuous bases for efficient target decay (Zhang et al. 2015, Yuan et al. 2016). In spite of this, the canonical post-transcriptional silencing by PIWI proteins has many similarities with other Argonaute-dependent RISC pathways that have been reviewed extensively elsewhere (Wilczynska & Bushell 2015). In addition to mediating classical RNA cleavage events, some studies have suggested that murine PIWIL1 can also direct target decay through recruitment of the deadenylase CAF1 during spermiogenesis (Fig. 2; Gou et al. 2014). For targeting through this mechanism, the requirement for piRISC-target complementarity is not strict and mismatches similar to those observed in miRNA-target interactions are possible (Gou et al. 2014). Follow-up studies will be required to determine the importance and scope of this pathway in cells where PIWIL1 is expressed.

Although it has been most widely studied in the context of post-transcriptional destruction of RNAs originating from genomic TE sequences, the PIWI pathway has also been implicated in TGS through directed DNA methylation and histone modifications (Fig. 1B; Carmell et al. 2007, Klenov et al. 2014). In studies with Drosophila, Piwi localization in both the nucleus and cytoplasm was demonstrated and Piwi depletion changed the pattern of chromatin silencing of specific TEs (Klenov et al. 2011). Subsequently, Piwi binding to nascent RNAs transcribed from target loci was shown to result in the deposition of repressive H3K9me3 marks on nearby histones (Le Thomas et al. 2013, Post et al. 2014). Further epigenetic influence was observed with a mutated, slicer-incompetent Piwi (incapable of endonucleolytic cleavage) which retained the ability to transcriptionally silence TE expression through the prevention of RNA Pol II occupancy at specific loci in conjunction with the cofactor Mael (Klenov et al. 2011, Sienski et al. 2012). Mammalian PIWIL4 has similar roles in transcriptional repression, but mediates changes in DNA methylation rather than altering histones (Aravin et al. 2008). One early hypothesis in which PIWIL2 was thought to generate piRNAs that subsequently bind to PIWIL4 and direct targeted methylation has recently been challenged by reports showing substantial differences in TE repression in mouse testes by PIWIL2 and PIWL4 (Manakov et al. 2015). While abundant evidence suggests that the PIWI pathway participates in both post-transcriptional and transcriptional TE silencing, it is important to note that the relative importance of the two processes is likely to vary with the stage of gamete differentiation or embryo development during which it is expressed, as demonstrated very recently during spermatogenesis (Inoue et al. 2017). The mechanisms and consequences of epigenetic changes directed by the PIWI pathway remain very active areas of investigation and are likely to yield fascinating insight into reprogramming and development.

Our understanding of the PIWI pathway has been most strongly and consistently informed by the many studies of its different roles in TE suppression. However, any review of this pathway would be incomplete without briefly mentioning several emerging roles for the pathway in the control of gene expression during gamete and embryo development. One of the first described examples of this phenomenon is presented in studies demonstrating PIWI-dependent, piRNA-directed DNA methylation of the paternally imprinted Rasgrf1 locus in mice (Watanabe et al. 2011b). Through targeting TE sequences within a differentially methylated region adjacent to this locus, piRNAs direct methylation and silencing. Importantly however, piRNAs do not direct all imprinting events, many of which are unaffected after PIWI pathway suppression (Watanabe et al. 2011b). While piRNA-directed imprinting processes appear to require TE sequences, several recent studies in gametes suggest that mRNAs can also act as direct PIWI pathway targets, particularly during spermatogenesis (Gou et al. 2014) and, more recently, in oocytes (Russell et al. 2017). The mechanisms through which such targeting has evolved and its overall importance in fertility and gamete development remain active fields of study.

Conclusions

The structure and function of non-coding regions of the genome, much of which consists of TE sequences, has only recently become the focus of intensive study. Normally, TEs are epigenetically silenced, but it has become apparent that their limited activation during reprogramming is an essential feature of gametogenesis and development, contributing directly to these processes through mechanisms that remain largely uncharacterized. The evolutionary advantages selecting for some level of TE expression may lie in the expanded regulatory potential they confer after reintegration within regulatory domains, a process that has contributed sequences to more than one quarter of human coding genes (Faulkner et al. 2009) and driven adaptive change. However, excessive TE activation is clearly detrimental and leads to infertility and developmental problems. These combined observations suggest that, rather than completely eliminating TE expression, control systems have evolved to promote a delicate balance between permission and suppression of TE activation during reprogramming. The characteristics of the PIWI pathway are consistent with this – TEs are suppressed only after the piRNAs that target them are transcribed and processed. A secondary amplification loop that depends on the presence of TE transcripts enhances suppression once initiated. Phasing and trimming of piRNAs during the biogenesis process expands the repertoire of targets and helps specify the nature of target suppression (post-transcriptional vs transcriptional). Evolutionary expansion of the PIWI pathway to target coding sequences, possibly as a consequence of TE integration into coding and transcriptional regulatory regions of the genome, have expanded functionality in ways we are only just beginning to understand. Future studies on the PIWI pathway will need to resolve a number of key issues; the identity of many cofactors in mammalian species, the factors that initiate piRNA biogenesis, particularly in somatic cells and the mechanisms by which they do so are particularly important questions. With respect to reproduction in particular, the overall importance of the PIWI pathway in mammalian oogenesis and embryogenesis remain unknown. However, regardless of the specific importance of the PIWI pathway itself in any one species, the ongoing tension between ancient virus sequences that hide within host DNA, and the defense pathways that keep them in check, continues to shape the genomic landscape and profoundly influence the control of gene expression that guides gametogenesis and the earliest phases of embryonic development.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

The authors wish to thank Clifford Librach, Leanne Stalker, Allison Tscherner, Graham Gilchrist, Pavneesh Madan and Allan King for helpful discussions. Studies on the PIWI pathway in gametes and embryos in the LaMarre laboratory have been supported by NSERC (Canada), the Ontario Ministry of Agriculture Food and Rural Affairs and by a Michelson Grant in Reproductive Biology from the Michelson Found Animals Foundation.

References

  • AdelsonDLRaisonJMEdgarRC 2009 Characterization and distribution of retrotransposons and simple sequence repeats in the bovine genome. PNAS 106 1285512860. (https://doi.org/10.1073/pnas.0901282106)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AdjayeJDanielsRBoltonVMonkM 1997 cDNA libraries from single human preimplantation embryos. Genomics 46 337344. (https://doi.org/10.1006/geno.1997.5117)

  • AlmeidaLMSilvaITSilvaWAJrCastroJPRiggsPKCararetoCMAmaralMEJ 2007 The contribution of transposable elements to Bos taurus gene structure. Gene 390 180189. (https://doi.org/10.1016/j.gene.2006.10.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AnHJLeeDLeeKHBhakJ 2004 The association of Alu repeats with the generation of potential AU-rich elements (ARE) at 3′ untranslated regions. BMC Genomics 5 97. (https://doi.org/10.1186/1471-2164-5-97)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AndersenPRTirianLVunjakMBrenneckeJ 2017 A heterochromatin-dependent transcription machinery drives piRNA expression. Nature 549 5459. (https://doi.org/10.1038/nature23482)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AravinAANaumovaNMTulinAVVaginVVRozovskyYMGvozdevVA 2001 Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Current Biology 11 10171027. (https://doi.org/10.1016/S0960-9822(01)00299-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AravinAGaidatzisDPfefferSLagos-QuintanaMLandgrafPIovinoNMorrisPBrownsteinMJKuramochi-MiyagawaSNakanoT 2006 A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442 203207. (https://doi.org/10.1038/nature04916)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • AravinAASachidanandamRGirardAFejes-TothKHannonGJ 2007a Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 316 744747. (https://doi.org/10.1126/science.1142612)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AravinAAHannonGJBrenneckeJ 2007b The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318 761764. (https://doi.org/10.1126/science.1146484)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AravinAASachidanandamRBourc’hisDSchaeferCPezicDTothKFBestorTHannonGJ 2008 A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Molecular Cell 31 785799. (https://doi.org/10.1016/j.molcel.2008.09.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AravinAAvan der HeijdenGWCastañedaJVaginVVHannonGJBortvinA 2009 Cytoplasmic compartmentalization of the fetal piRNA pathway in mice. PLoS Genetics 5 e1000764. (https://doi.org/10.1371/journal.pgen.1000764)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BarreauCPaillardLOsborneHB 2005 AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Research 33 71387150. (https://doi.org/10.1093/nar/gki1012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BeckCRGarcia-PerezJLBadgeRMMoranJV 2011 LINE-1 elements in structural variation and disease. Annual Review of Genomics and Human Genetics 12 187215. (https://doi.org/10.1146/annurev-genom-082509-141802)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BejeranoGLoweCBAhituvNKingBSiepelASalamaSRRubinEMKentWJHausslerD 2006 A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441 8790. (https://doi.org/10.1038/nature04696)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BelancioVPRoy-EngelAMDeiningerPL 2010 All y’all need to know ‘bout retroelements in cancer. Seminars in Cancer Biology 20 200210. (https://doi.org/10.1016/j.semcancer.2010.06.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BenachenhouFJernPOjaMSperberGBlikstadVSomervuoPKaskiSBlombergJ 2009 Evolutionary conservation of orthoretroviral long terminal repeats (LTRs) and ab initio detection of single LTRs in genomic data. PLoS ONE 4 e5179. (https://doi.org/10.1371/journal.pone.0005179)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BeraldiRPittoggiCSciamannaIMatteiESpadaforaC 2006 Expression of LINE-1 retroposons is essential for murine preimplantation development. Molecular Reproduction and Development 73 279287. (https://doi.org/10.1002/mrd.20423)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BrenneckeJAravinAAStarkADusMKellisMSachidanandamRHannonGJ 2007 Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128 10891103. (https://doi.org/10.1016/j.cell.2007.01.043)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BuchanJRParkerR 2009 Eukaryotic stress granules: the ins and outs of translation. Molecular Cell 36 932941. (https://doi.org/10.1016/j.molcel.2009.11.020)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BuiLCEvsikovAVKhanDRArchillaCPeynotNHénautALe BourhisDVignonXRenardJPDuranthonV 2009 Retrotransposon expression as a defining event of genome reprogramming in fertilized and cloned bovine embryos. Reproduction 138 289299. (https://doi.org/10.1530/REP-09-0042)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BuzdinAGogvadzeEKovalskayaEVolchkovPUstyugovaSIllarionovaAFushanAVinogradovaTSverdlovE 2003 The human genome contains many types of chimeric retrogenes generated through in vivo RNA recombination. Nucleic Acids Research 31 43854390. (https://doi.org/10.1093/nar/gkg496)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CapyPGasperiGBiémontCBazinC 2000 Stress and transposable elements: co-evolution or useful parasites? Heredity 85 101106. (https://doi.org/10.1046/j.1365-2540.2000.00751.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CarmellMAGirardAvan de KantHJGBourc’hisDBestorTHde RooijDGHannonGJ 2007 MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Developmental Cell 12 503514. (https://doi.org/10.1016/j.devcel.2007.03.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ChenCJinJJamesDAAdams-CioabaMAParkJGGuoYTenagliaEXuCGishGMinJ 2009 Mouse Piwi interactome identifies binding mechanism of Tdrkh Tudor domain to arginine methylated Miwi. PNAS 106 2033620341. (https://doi.org/10.1073/pnas.0911640106)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ChenCLiuJXuG 2013 Overexpression of PIWI proteins in human stage III epithelial ovarian cancer with lymph node metastasis. Cancer Biomarkers: Section A of Disease Markers 13 315321. (https://doi.org/10.3233/CBM-130360)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CoraEPandeyRRXiolJTaylorJSachidanandamRMcCarthyAAPillaiRS 2014 The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs. RNA 20 773781. (https://doi.org/10.1261/rna.044701.114)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CoxDNChaoABakerJChangLQiaoDLinH 1998 A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes and Development 12 37153727. (https://doi.org/10.1101/gad.12.23.3715)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CzechBHannonGJ 2016 One loop to rule them all: the ping-pong cycle and piRNA-guided silencing. Trends in Biochemical Sciences 41 324337. (https://doi.org/10.1016/j.tibs.2015.12.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • De FazioSBartonicekNDi GiacomoMAbreu-GoodgerCSankarAFunayaCAntonyCMoreiraPNEnrightAJO’CarrollD 2011 The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements. Nature 480 259263. (https://doi.org/10.1038/nature10547)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • DeiningerPL 2002 Mammalian retroelements. Genome Research 12 14551465. (https://doi.org/10.1101/gr.282402)

  • DeiningerPL 2011 Alu elements: know the SINEs. Genome Biology 12 236. (https://doi.org/10.1186/gb-2011-12-12-236)

  • DeiningerPLMoranJVBatzerMAKazazianHHJr 2003 Mobile elements and mammalian genome evolution. Current Opinion in Genetics and Development 13 651658. (https://doi.org/10.1016/j.gde.2003.10.013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • DengWLinH 2002 Miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis. Developmental Cell 2 819830. (https://doi.org/10.1016/S1534-5807(02)00165-X)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • DönertasDSienskiGBrenneckeJ 2013 Drosophila Gtsf1 is an essential component of the Piwi-mediated transcriptional silencing complex. Genes and Development 27 16931705. (https://doi.org/10.1101/gad.221150.113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ElbarbaryRALucasBAMaquatLE 2016 Retrotransposons as regulators of gene expression. Science 351 aac7247. (https://doi.org/10.1126/science.aac7247)

  • EymeryALiuZOzonovEAStadlerMBPetersAHFM 2016 The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos. Development 143 27672779. (https://doi.org/10.1242/dev.132746)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FaulknerGJKimuraYDaubCOWaniSPlessyCIrvineKMSchroderKCloonanNSteptoeALLassmannT 2009 The regulated retrotransposon transcriptome of mammalian cells. Nature Genetics 41 563571. (https://doi.org/10.1038/ng.368)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FedoroffNV 2012 Presidential address. Transposable elements, epigenetics, and genome evolution. Science 338 758767. (https://doi.org/10.1126/science.338.6108.758)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FlemrMMalikRFrankeVNejepinskaJSedlacekRVlahovicekKSvobodaP 2013 A retrotransposon-driven dicer isoform directs endogenous small interfering RNA production in mouse oocytes. Cell 155 807816. (https://doi.org/10.1016/j.cell.2013.10.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FrankeVGaneshSKarlicRMalikRPasulkaJHorvatFKuzmanMFulkaHCernohorskaMUrbanovaJ 2017 Long terminal repeats power evolution of genes and gene expression programs in mammalian oocytes and zygotes. Genome Research 27 13841394. (https://doi.org/10.1101/gr.216150.116)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • FrostRJAHamraFKRichardsonJAQiXBassel-DubyROlsonEN 2010 MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs. PNAS 107 1184711852. (https://doi.org/10.1073/pnas.1007158107)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Garcia-EtxebarriaKJugoBM 2010 Genome-wide detection and characterization of endogenous retroviruses in Bos taurus. Journal of Virology 84 1085210862. (https://doi.org/10.1128/JVI.00106-10)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GeSX 2017 Exploratory bioinformatics investigation reveals importance of ‘junk’ DNA in early embryo development. BMC Genomics 18 200. (https://doi.org/10.1186/s12864-017-3566-0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GebertDKettingRFZischlerHRosenkranzD 2015 piRNAs from pig testis provide evidence for a conserved role of the piwi pathway in post-transcriptional gene regulation in mammals. PLoS ONE 10 e0124860. (https://doi.org/10.1371/journal.pone.0124860)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GirardASachidanandamRHannonGJCarmellMA 2006 A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442 199202.

  • GoriauxCDessetSRenaudYVauryCBrassetE 2014 Transcriptional properties and splicing of the flamenco piRNA cluster. EMBO Reports 15 411418. (https://doi.org/10.1002/embr.201337898)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GouL-TDaiPYangJ-HXueYHuY-PZhouYKangJ-YWangXLiHHuaM-M 2014 Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis. Cell Research 24 680700. (https://doi.org/10.1038/cr.2014.41)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GrowEJFlynnRAChavezSLBaylessNLWossidloMWescheDJMartinLWareCBBlishCAChangHY 2015 Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 522 221225. (https://doi.org/10.1038/nature14308)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GunawardaneLSSaitoKNishidaKMMiyoshiKKawamuraYNagamiTSiomiHSiomiMC 2007 A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science 315 15871590. (https://doi.org/10.1126/science.1140494)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • GuoHZhuPYanLLiRHuBLianYYanJRenXLinSLiJ 2014 The DNA methylation landscape of human early embryos. Nature 511 606610. (https://doi.org/10.1038/nature13544)

  • HanBWHungJ-HWengZZamorePDAmeresSL 2011 The 3′-to-5′ exoribonuclease Nibbler shapes the 3′ ends of microRNAs bound to Drosophila Argonaute. Current Biology 21 18781887. (https://doi.org/10.1016/j.cub.2011.09.034)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • HanBWWangWLiCWengZZamorePD 2015 Noncoding RNA. piRNA-guided transposon cleavage initiates Zucchini-dependent, phased piRNA production. Science 348 817821. (https://doi.org/10.1126/science.aaa1264)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HarrisANMacdonaldPM 2001 Aubergine encodes a Drosophila polar granule component required for pole cell formation and related to eIF2C. Development 128 28232832.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • HayashiRSchnablJHandlerDMohnFAmeresSLBrenneckeJ 2016 Genetic and mechanistic diversity of piRNA 3′-end formation. Nature 539 588592. (https://doi.org/10.1038/nature20162)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HendricksonPGDoráisJAGrowEJWhiddonJLLimJ-WWikeCLWeaverBDPfluegerCEmeryBRWilcoxAL 2017 Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nature Genetics 49 925934. (https://doi.org/10.1038/ng.3844)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HickmanABDydaF 2015 Mechanisms of DNA transposition. In Mobile DNA III. Eds N Craig M Chandler M Gellert A Lambowitz P Rice and S Sandmeyer; ASM Press: Washington DC, USA. (https://doi.org/10.1128/microbiolspec.MDNA3-0034-2014)

    • Search Google Scholar
    • Export Citation
  • HirakataSSiomiMC 2016 piRNA biogenesis in the germline: from transcription of piRNA genomic sources to piRNA maturation. Biochimica et Biophysica Acta 1859 8292. (https://doi.org/10.1016/j.bbagrm.2015.09.002)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HoltJERomanSDAitkenRJMcLaughlinEA 2006 Identification and characterization of a novel Mt-retrotransposon highly represented in the female mouse germline. Genomics 87 490499. (https://doi.org/10.1016/j.ygeno.2005.08.015)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HondaSKirinoYMaragkakisMAlexiouPOhtakiAMuraliRMourelatosZKirinoY 2013 Mitochondrial protein BmPAPI modulates the length of mature piRNAs. RNA 19 14051418. (https://doi.org/10.1261/rna.040428.113)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HorwichMDLiCMatrangaCVaginVFarleyGWangPZamorePD 2007 The Drosophila RNA methyltransferase, DmHen1, modifies germline piRNAs and single-stranded siRNAs in RISC. Current Biology 17 12651272. (https://doi.org/10.1016/j.cub.2007.06.030)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • HouwingSKammingaLMBerezikovECronemboldDGirardAvan den ElstHFilippovDVBlaserHRazEMoensCB 2007 A role for Piwi and piRNAs in germ cell maintenance and transposon silencing in Zebrafish. Cell 129 6982. (https://doi.org/10.1016/j.cell.2007.03.026)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HuangYKimJKDoDVLeeCPenfoldCAZyliczJJMarioniJCHackettJASuraniMA 2017 Stella modulates transcriptional and endogenous retrovirus programs during maternal-to-zygotic transition. eLife 6 e22345. (https://doi.org/10.7554/eLife.22345)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • HudaAMariño-RamírezLJordanIK 2010 Epigenetic histone modifications of human transposable elements: genome defense versus exaptation. Mobile DNA 1 2. (https://doi.org/10.1186/1759-8753-1-2)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • InoueKIchiyanagiKFukudaKGlinkaMSasakiH 2017 Switching of dominant retrotransposon silencing strategies from posttranscriptional to transcriptional mechanisms during male germ-cell development in mice. PLoS Genetics 13 e1006926. (https://doi.org/10.1371/journal.pgen.1006926)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • IpsaroJJHaaseADKnottSRJoshua-TorLHannonGJ 2012 The structural biochemistry of Zucchini implicates it as a nuclease in piRNA biogenesis. Nature 491 279283. (https://doi.org/10.1038/nature11502)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • IshizuHSiomiHSiomiMC 2012 Biology of PIWI-interacting RNAs: new insights into biogenesis and function inside and outside of germlines. Genes and Development 26 23612373. (https://doi.org/10.1101/gad.203786.112)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • IzumiNKawaokaSYasuharaSSuzukiYSuganoSKatsumaSTomariY 2013 Hsp90 facilitates accurate loading of precursor piRNAs into PIWI proteins. RNA 19 896901. (https://doi.org/10.1261/rna.037200.112)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • JachowiczJWBingXPontabryJBoškovićARandoOJTorres-PadillaM-E 2017 LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nature Genetics 49 15021510. (https://doi.org/10.1038/ng.3945)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KawaokaSIzumiNKatsumaSTomariY 2011 3′ end formation of PIWI-interacting RNAs in vitro. Molecular Cell 43 10151022. (https://doi.org/10.1016/j.molcel.2011.07.029)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KazazianHH 1998 Mobile elements and disease. Current Opinion in Genetics and Development 8 343350. (https://doi.org/10.1016/S0959-437X(98)80092-0)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KazazianHHJrWongCYoussoufianHScottAFPhillipsDGAntonarakisSE 1988 Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332 164166. (https://doi.org/10.1038/332164a0)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KigamiDMinamiNTakayamaHImaiH 2003 MuERV-L is one of the earliest transcribed genes in mouse one-cell embryos. Biology of Reproduction 68 651654. (https://doi.org/10.1095/biolreprod.102.007906)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KlenovMSSokolovaOAYakushevEYStolyarenkoADMikhalevaEALavrovSAGvozdevVA 2011 Separation of stem cell maintenance and transposon silencing functions of Piwi protein. PNAS 108 1876018765. (https://doi.org/10.1073/pnas.1106676108)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KlenovMSLavrovSAKorbutAPStolyarenkoADYakushevEYReuterMPillaiRSGvozdevVA 2014 Impact of nuclear Piwi elimination on chromatin state in Drosophila melanogaster ovaries. Nucleic Acids Research 42 62086218. (https://doi.org/10.1093/nar/gku268)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KroutterENBelancioVPWagstaffBJRoy-EngelAM 2009 The RNA polymerase dictates ORF1 requirement and timing of LINE and SINE retrotransposition. PLoS Genetics 5 e1000458. (https://doi.org/10.1371/journal.pgen.1000458)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • KulkarniMOzgurSStoecklinG 2010 On track with P-bodies. Biochemical Society Transactions 38 242251. (https://doi.org/10.1042/BSbib380242)

  • Kuramochi-MiyagawaSKimuraTIjiriTWIsobeTAsadaNFujitaYIkawaMIwaiNOkabeMDengW 2004 Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development 131 839849. (https://doi.org/10.1242/dev.00973)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kuramochi-MiyagawaSWatanabeTGotohKTotokiYToyodaAIkawaMAsadaNKojimaKYamaguchiYIjiriTW 2008 DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes and Development 22 908917. (https://doi.org/10.1101/gad.1640708)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kuramochi-MiyagawaSWatanabeTGotohKTakamatsuKChumaSKojima-KitaKShiromotoYAsadaNToyodaAFujiyamaA 2010 MVH in piRNA processing and gene silencing of retrotransposons. Genes and Development 24 887892. (https://doi.org/10.1101/gad.1902110)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • KwonCTakHRhoMChangHRKimYHKimKTBalchCLeeEKNamS 2014 Detection of PIWI and piRNAs in the mitochondria of mammalian cancer cells. Biochemical and Biophysical Research Communications 446 218223. (https://doi.org/10.1016/j.bbrc.2014.02.112)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LanderESLintonLMBirrenBNusbaumCZodyMCBaldwinJDevonKDewarKDoyleMFitzHughW 2001 Initial sequencing and analysis of the human genome. Nature 409 860921. (https://doi.org/10.1038/35057062)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LauNCSetoAGKimJKuramochi-MiyagawaSNakanoTBartelDPKingstonRE 2006 Characterization of the piRNA complex from rat testes. Science 313 363367. (https://doi.org/10.1126/science.1130164)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lees-MurdockDJDe FeliciMWalshCP 2003 Methylation dynamics of repetitive DNA elements in the mouse germ cell lineage. Genomics 82 230237. (https://doi.org/10.1016/S0888-7543(03)00105-8)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Le ThomasARogersAKWebsterAMarinovGKLiaoSEPerkinsEMHurJKAravinAATóthKF 2013 Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. Genes and Development 27 390399. (https://doi.org/10.1101/gad.209841.112)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • LeungDCLorinczMC 2012 Silencing of endogenous retroviruses: when and why do histone marks predominate? Trends in Biochemical Sciences 37 127133. (https://doi.org/10.1016/j.tibs.2011.11.006)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiXZRoyCKDongXBolcun-FilasEWangJHanBWXuJMooreMJSchimentiJCWengZ 2013 An ancient transcription factor initiates the burst of piRNA production during early meiosis in mouse testes. Molecular Cell 50 6781. (https://doi.org/10.1016/j.molcel.2013.02.016)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiWGoossensKVan PouckeMForierKBraeckmansKVan SoomAPeelmanLJ 2016 High oxygen tension increases global methylation in bovine 4-cell embryos and blastocysts but does not affect general retrotransposon expression. Reproduction Fertility and Development 28 948959. (https://doi.org/10.1071/RD14133)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LiPWangLBennettBDWangJLiJQinYTakakuMWadePAWongJHuG 2017 Rif1 promotes a repressive chromatin state to safeguard against endogenous retrovirus activation. Nucleic Acids Research 45 1272312738. (https://doi.org/10.1093/nar/gkx884)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LimAKKaiT 2007 Unique germ-line organelle, nuage, functions to repress selfish genetic elements in Drosophila melanogaster. PNAS 104 67146719. (https://doi.org/10.1073/pnas.0701920104)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • LimAKLorthongpanichCChewTGTanCWGShueYTBaluSGounkoNKuramochi-MiyagawaSMatzukMMChumaS 2013 The nuage mediates retrotransposon silencing in mouse primordial ovarian follicles. Development 140 38193825. (https://doi.org/10.1242/dev.099184)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • LinHSpradlingAC 1997 A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. Development 124 24632476.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • LuoY-BZhangLLinZ-LMaJ-YJiaJNamgoongSSunQ-Y 2016 Distinct subcellular localization and potential role of LINE1-ORF1P in meiotic oocytes. Histochemistry and Cell Biology 145 93104. (https://doi.org/10.1007/s00418-015-1369-4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MaatoukDMKellamLDMannMRWLeiHLiEBartolomeiMSResnickJL 2006 DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages. Development 133 34113418. (https://doi.org/10.1242/dev.02500)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MaksakovaIARomanishMTGagnierLDunnCAVan De LagemaatLNMagerDL 2006 Retroviral elements and their hosts: Insertional mutagenesis in the mouse germ line. PLoS Genetics 2 110. (https://doi.org/10.1371/journal.pgen.0020001)

    • Search Google Scholar
    • Export Citation
  • MalkiSvan der HeijdenGWO’DonnellKAMartinSLBortvinA 2014 A role for retrotransposon LINE-1 in fetal oocyte attrition in mice. Developmental Cell 29 521533. (https://doi.org/10.1016/j.devcel.2014.04.027)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MaloneCDBrenneckeJDusMStarkAMcCombieWRSachidanandamRHannonGJ 2009 Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137 522535. (https://doi.org/10.1016/j.cell.2009.03.040)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ManakovSAPezicDMarinovGKPastorWASachidanandamRAravinAA 2015 MIWI2 and MILI have differential effects on piRNA biogenesis and DNA methylation. Cell Reports 12 12341243. (https://doi.org/10.1016/j.celrep.2015.07.036)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MartinSL 2006 The ORF1 protein encoded by LINE-1: structure and function during L1 retrotransposition. Journal of Biomedicine and Biotechnology 2006 45621. (https://doi.org/10.1155/JBB/2006/45621)

    • Search Google Scholar
    • Export Citation
  • McClintockB 1950 The origin and behavior of mutable loci in maize. PNAS 36 344355. (https://doi.org/10.1073/pnas.36.6.344)

  • MeikarOVaginVVChalmelFSõstarKLardenoisAHammellMJinYDa RosMWasikKAToppariJ 2014 An atlas of chromatoid body components. RNA 20 483495. (https://doi.org/10.1261/rna.043729.113)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MohnFSienskiGHandlerDBrenneckeJ 2014 The rhino-deadlock-cutoff complex licenses noncanonical transcription of dual-strand piRNA clusters in Drosophila. Cell 157 13641379. (https://doi.org/10.1016/j.cell.2014.04.031)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MohnFHandlerDBrenneckeJ 2015 Noncoding RNA. piRNA-guided slicing specifies transcripts for Zucchini-dependent, phased piRNA biogenesis. Science 348 812817. (https://doi.org/10.1126/science.aaa1039)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • MorganHDSantosFGreenKDeanWReikW 2005 Epigenetic reprogramming in mammals. Human Molecular Genetics 14 R47R58. (https://doi.org/10.1093/hmg/ddi114)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • NandiSChandramohanDFioritiLMelnickAMHébertJMMasonCERajasethupathyPKandelER 2016 Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain. PNAS 113 1269712702. (https://doi.org/10.1073/pnas.1609287113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • NishimasuHIshizuHSaitoKFukuharaSKamataniMKBonnefondLMatsumotoNNishizawaTNakanagaKAokiJ 2012 Structure and function of Zucchini endoribonuclease in piRNA biogenesis. Nature 491 284287. (https://doi.org/10.1038/nature11509)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • OhtaniHIwasakiYWShibuyaASiomiHSiomiMCSaitoK 2013 DmGTSF1 is necessary for Piwi-piRISC-mediated transcriptional transposon silencing in the Drosophila ovary. Genes and Development 27 16561661. (https://doi.org/10.1101/gad.221515.113)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • OlivieriDSentiK-ASubramanianSSachidanandamRBrenneckeJ 2012 The cochaperone shutdown defines a group of biogenesis factors essential for all piRNA populations in Drosophila. Molecular Cell 47 954969. (https://doi.org/10.1016/j.molcel.2012.07.021)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • OnoMKawakamiMUshikuboH 1987 Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D. Journal of Virology 61 20592062.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • OstertagEMKazazianHHJr 2001 Biology of mammalian L1 retrotransposons. Annual Review of Genetics 35 501538. (https://doi.org/10.1146/annurev.genet.35.102401.091032)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • OstertagEMGoodierJLZhangYKazazianHHJr 2003 SVA elements are nonautonomous retrotransposons that cause disease in humans. American Journal of Human Genetics 73 14441451. (https://doi.org/10.1086/380207)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PaneAWehrKSchüpbachT 2007 zucchini and squash encode two putative nucleases required for rasiRNA production in the Drosophila germline. Developmental Cell 12 851862. (https://doi.org/10.1016/j.devcel.2007.03.022)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ParkC-EShinM-RJeonE-HLeeS-HChaK-YKimKKimN-HLeeK-A 2004 Oocyte-selective expression of MT transposon-like element, clone MTi7 and its role in oocyte maturation and embryo development. Molecular Reproduction and Development 69 365374. (https://doi.org/10.1002/mrd.20179)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PatilVSKaiT 2010 Repression of retroelements in Drosophila germline via piRNA pathway by the Tudor domain protein Tejas. Current Biology 20 724730. (https://doi.org/10.1016/j.cub.2010.02.046)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • PayerBSaitouMBartonSCThresherRDixonJPCZahnDColledgeWHCarltonMBLNakanoTSuraniMA 2003 Stella is a maternal effect gene required for normal early development in mice. Current Biology 13 21102117. (https://doi.org/10.1016/j.cub.2003.11.026)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • PeastonAEEvsikovAVGraberJHde VriesWNHolbrookAESolterDKnowlesBB 2004 Retrotransposons regulate host genes in mouse oocytes and preimplantation embryos. Developmental Cell 7 597606. (https://doi.org/10.1016/j.devcel.2004.09.004)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • PillaiRSChumaS 2012 piRNAs and their involvement in male germline development in mice. Development Growth and Differentiation 54 7892. (https://doi.org/10.1111/j.1440-169X.2011.01320.x)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • PostCClarkJPSytnikovaYAChirnG-WLauNC 2014 The capacity of target silencing by Drosophila PIWI and piRNAs. RNA 20 19771986. (https://doi.org/10.1261/rna.046300.114)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RajasethupathyPAntonovISheridanRFreySSanderCTuschlTKandelER 2012 A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. Cell 149 693707. (https://doi.org/10.1016/j.cell.2012.02.057)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ReuterMChumaSTanakaTFranzTStarkAPillaiRS 2009 Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile. Nature Structural and Molecular Biology 16 639646. (https://doi.org/10.1038/nsmb.1615)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ReuterMBerningerPChumaSShahHHosokawaMFunayaCAntonyCSachidanandamRPillaiRS 2011 Miwi catalysis is required for piRNA amplification-independent LINE1 transposon silencing. Nature 480 264267. (https://doi.org/10.1038/nature10672)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RooversEFRosenkranzDMahdipourMHanC-THeNChuva de Sousa LopesSMvan der WesterlakenLAJZischlerHButterFRoelenBAJ 2015 Piwi proteins and piRNAs in mammalian oocytes and early embryos. Cell Reports 10 20692082. (https://doi.org/10.1016/j.celrep.2015.02.062)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RussellSJStalkerLGilchristGBackxAMolledoGFosterRALaMarreJ 2016 Identification of PIWIL1 isoforms and their expression in bovine testes, oocytes, and early embryos. Biology of Reproduction 94 75. (https://doi.org/10.1095/biolreprod.115.136721)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • RussellSPatelMGilchristGStalkerLGillisDRosenkranzDLaMarreJ 2017 Bovine piRNA-like RNAs are associated with both transposable elements and mRNAs. Reproduction 153 305318. (https://doi.org/10.1530/REP-16-0620)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • RyanFP 2004 Human endogenous retroviruses in health and disease: a symbiotic perspective. Journal of the Royal Society of Medicine 97 560565. (https://doi.org/10.1177/014107680409701202)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SaitoKNishidaKMMoriTKawamuraYMiyoshiKNagamiTSiomiHSiomiMC 2006 Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome. Genes and Development 20 22142222. (https://doi.org/10.1101/gad.1454806)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SaitoKSakaguchiYSuzukiTSuzukiTSiomiHSiomiMC 2007 Pimet, the Drosophila homolog of HEN1, mediates 2′-O-methylation of Piwi-interacting RNAs at their 3′ ends. Genes and Development 21 16031608. (https://doi.org/10.1101/gad.1563607)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SaxeJPChenMZhaoHLinH 2013 Tdrkh is essential for spermatogenesis and participates in primary piRNA biogenesis in the germline. EMBO Journal 32 18691885. (https://doi.org/10.1038/emboj.2013.121)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SchiffRItinAKeshetE 1991 Transcriptional activation of mouse retrotransposons in vivo: specific expression in steroidogenic cells in response to trophic hormones. Genes and Development 5 521532. (https://doi.org/10.1101/gad.5.4.521)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • SchornAJGutbrodMJLeBlancCMartienssenR 2017 LTR-retrotransposon control by tRNA-derived small RNAs. Cell 170 61.e1171.e11. (https://doi.org/10.1016/j.cell.2017.06.013)

    • Search Google Scholar
    • Export Citation
  • SentiK-AJurczakDSachidanandamRBrenneckeJ 2015 piRNA-guided slicing of transposon transcripts enforces their transcriptional silencing via specifying the nuclear piRNA repertoire. Genes and Development 29 17471762. (https://doi.org/10.1101/gad.267252.115)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ShenH 2009 UAP56-a key player with surprisingly diverse roles in pre-mRNA splicing and nuclear export. BMB Reports 42 185188. (https://doi.org/10.5483/BMBRep.2009.42.4.185)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ShojiMTanakaTHosokawaMReuterMStarkAKatoYKondohGOkawaKChujoTSuzukiT 2009 The TDRD9-MIWI2 complex is essential for piRNA-mediated retrotransposon silencing in the mouse male germline. Developmental Cell 17 775787. (https://doi.org/10.1016/j.devcel.2009.10.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SienskiGDönertasDBrenneckeJ 2012 Transcriptional silencing of transposons by Piwi and maelstrom and its impact on chromatin state and gene expression. Cell 151 964980. (https://doi.org/10.1016/j.cell.2012.10.040)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SokolMJessenKMPedersenFS 2015 Human endogenous retroviruses sustain complex and cooperative regulation of gene-containing loci and unannotated megabase-sized regions. Retrovirology 12 32. (https://doi.org/10.1186/s12977-015-0161-9)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • StalkerLRussellSJCoCFosterRALaMarreJ 2016 PIWIL1 is expressed in the canine testis, increases with sexual maturity, and binds small RNAs. Biology of Reproduction 94 17. (https://doi.org/10.1095/biolreprod.115.131854)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • StanleyDFraserSStanleyGAChambersPJ 2010 Retrotransposon expression in ethanol-stressed Saccharomyces cerevisiae. Applied Microbiology and Biotechnology 87 14471454. (https://doi.org/10.1007/s00253-010-2562-y)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SteinPRozhkovNVLiFCárdenasFLDavydenkoODavydenkOVandivierLEGregoryBDHannonGJSchultzRM 2015 Essential role for endogenous siRNAs during meiosis in mouse oocytes. PLoS Genetics 11 e1005013. (https://doi.org/10.1371/journal.pgen.1005013)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • StoyeJP 2012 Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nature Reviews: Microbiology 10 395406.

  • SuY-QSugiuraKSunFPendolaJKCoxGAHandelMASchimentiJCEppigJJ 2012 MARF1 regulates essential oogenic processes in mice. Science 335 14961499. (https://doi.org/10.1126/science.1214680)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • SwergoldGD 1990 Identification, characterization, and cell specificity of a human LINE-1 promoter. Molecular and Cellular Biology 10 67186729. (https://doi.org/10.1128/MCB.10.12.6718)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TaoYYenM-RChitiashviliTNakanoHKimRHosohamaLTanYCNakanoAChenP-YClarkAT 2018 TRIM28-regulated transposon repression is required for human germline competency and not primed or naive human pluripotency. Stem Cell Reports 10 243256. (https://doi.org/10.1016/j.stemcr.2017.11.020)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • TöhönenVKatayamaSVesterlundLJouhilahtiE-MSheikhiMMadissoonEFilippini-CattaneoGJaconiMJohnssonABürglinTR 2015 Novel PRD-like homeodomain transcription factors and retrotransposon elements in early human development. Nature Communications 6 8207. (https://doi.org/10.1038/ncomms9207)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • VaginVVSigovaALiCSeitzHGvozdevVZamorePD 2006 A distinct small RNA pathway silences selfish genetic elements in the germline. Science 313 320324. (https://doi.org/10.1126/science.1129333)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • van de LagemaatLNLandryJ-RMagerDLMedstrandP 2003 Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions. Trends in Genetics 19 530536. (https://doi.org/10.1016/j.tig.2003.08.004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Virant-KlunILeichtSHughesCKrijgsveldJ 2016 Identification of maturation-specific proteins by single-cell proteomics of human oocytes. Molecular and Cellular Proteomics 15 26162627. (https://doi.org/10.1074/mcp.M115.056887)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • VourekasAZhengQAlexiouPMaragkakisMKirinoYGregoryBDMourelatosZ 2012 Mili and Miwi target RNA repertoire reveals piRNA biogenesis and function of Miwi in spermiogenesis. Nature Structural and Molecular Biology 19 773781. (https://doi.org/10.1038/nsmb.2347)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • VourekasAZhengKFuQMaragkakisMAlexiouPMaJPillaiRSMourelatosZWangPJ 2015 The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing. Genes and Development 29 617629. (https://doi.org/10.1101/gad.254631.114)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WangHMaZNiuKXiaoYWuXPanCZhaoYWangKZhangYLiuN 2016 Antagonistic roles of Nibbler and Hen1 in modulating piRNA 3′ ends in Drosophila. Development 143 530539. (https://doi.org/10.1242/dev.128116)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • WatanabeTTotokiYToyodaAKanedaMKuramochi-MiyagawaSObataYChibaHKoharaYKonoTNakanoT 2008 Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453 539543. (https://doi.org/10.1038/nature06908)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • WatanabeTChumaSYamamotoYKuramochi-MiyagawaSTotokiYToyodaAHokiYFujiyamaAShibataTSadoT 2011a MITOPLD is a mitochondrial protein essential for nuage formation and piRNA biogenesis in the mouse germline. Developmental Cell 20 364375. (https://doi.org/10.1016/j.devcel.2011.01.005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WatanabeTTomizawaS-IMitsuyaKTotokiYYamamotoYKuramochi-MiyagawaSIidaNHokiYMurphyPJToyodaA 2011b Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science 332 848852. (https://doi.org/10.1126/science.1203919)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WesslerSR 1996 Turned on by stress. Plant retrotransposons. Current Biology 6 959961. (https://doi.org/10.1016/S0960-9822(02)00638-3)

  • WickerTSabotFHua-VanABennetzenJLCapyPChalhoubBFlavellALeroyPMorganteMPanaudO 2007 A unified classification system for eukaryotic transposable elements. Nature Reviews: Genetics 8 973982. (https://doi.org/10.1038/nrg2165)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • WickerTSabotFHua-VanABennetzenJLCapyPChalhoubBFlavellALeroyPMorganteMPanaudO 2008 A universal classification of eukaryotic transposable elements implemented in Repbase. Nature Reviews: Genetics 9 414414. (https://doi.org/10.1038/nrg2165-c2)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WilczynskaABushellM 2015 The complexity of miRNA-mediated repression. Cell Death and Differentiation 22 2233. (https://doi.org/10.1038/cdd.2014.112)

  • WilliamsRWRubinGM 2002 ARGONAUTE1 is required for efficient RNA interference in Drosophila embryos. PNAS 99 68896894. (https://doi.org/10.1073/pnas.072190799)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • WilsonJEConnellJEMacdonaldPM 1996 Aubergine enhances oskar translation in the Drosophila ovary. Development 122 16311639.

  • XiolJSpinelliPLaussmannMAHomolkaDYangZCoraECoutéYConnSKadlecJSachidanandamR 2014 RNA clamping by Vasa assembles a piRNA amplifier complex on transposon transcripts. Cell 157 16981711. (https://doi.org/10.1016/j.cell.2014.05.018)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • YoshimuraTWatanabeTKuramochi-MiyagawaSTakemotoNShiromotoYKudoAKanai-AzumaMTashiroFMiyazakiSKatanayaA 2018 Mouse GTSF1 is an essential factor for secondary piRNA biogenesis. EMBO Reports 19 e42054. (https://doi.org/10.15252/embr.201642054)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • YuanJZhangPCuiYWangJSkogerbøGHuangD-WChenRHeS 2016 Computational identification of piRNA targets on mouse mRNAs. Bioinformatics 32 11701177. (https://doi.org/10.1093/bioinformatics/btv729)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZamudioNBarauJTeissandierAWalterMBorsosMServantNBourc’hisD 2015 DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination. Genes and Development 29 12561270. (https://doi.org/10.1101/gad.257840.114)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ZhangZXuJKoppetschBSWangJTippingCMaSWengZTheurkaufWEZamorePD 2011 Heterotypic piRNA Ping-Pong requires qin, a protein with both E3 ligase and Tudor domains. Molecular Cell 44 572584. (https://doi.org/10.1016/j.molcel.2011.10.011)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhangFWangJXuJZhangZKoppetschBSSchultzNVrevenTMeigninCDavisIZamorePD 2012 UAP56 couples piRNA clusters to the perinuclear transposon silencing machinery. Cell 151 871884. (https://doi.org/10.1016/j.cell.2012.09.040)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhangPKangJ-YGouL-TWangJXueYSkogerboeGDaiPHuangD-WChenRFuX-D 2015 MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Research 25 193207. (https://doi.org/10.1038/cr.2015.4)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ZhangHLiuJTaiYZhangXZhangJLiuSLvJLiuZKongQ 2017 Identification and characterization of L1-specific endo-siRNAs essential for early embryonic development in pig. Oncotarget 8 2316723176. (https://doi.org/10.18632/oncotarget.15517)

    • PubMed
    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

    Society for Reproduction and Fertility

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1353 1208 44
PDF Downloads 443 372 19

Altmetrics

Figures

  • View in gallery

    Structure and activty of common mammalian transposable elements (TEs). Note: Due to the generally dispensable nature of most TEs, there are many permutations of the structures described here. (A) Long and short interspersed nuclear elements (LINEs and SINEs) are flanked by target site duplications due to the mechanism of LINE1 retrotransposition. Transcription of LINE1 is initiated after association of RNA polymerase (RNA pol) II with the TE promoter sequence (black bent arrow) in the 5′ UTR. Complete copies encode two open reading frames (ORF1 and ORF2), followed by the 3′ UTR and poly(A) tail. Both ORF1 and ORF2 are required for LINE1 retrotransposition; the former encoding a nucleic acid chaperone and the latter a protein with endonuclease (EN) and reverse transcriptase (RT) domains. SINEs are dependent on LINE1 ORF2 for retrotransposition, and do not encode proteins. Their structures are highly variable, but two conserved primate elements are presented here: Alu and SVA. Alu is transcribed by RNA pol III from a promoter (gray bent arrow) in the left monomer, which terminates downstream of the element at the closest genomic terminator sequence (poly(T)). Alu contains two monomers that form independent secondary RNA structures, an A-rich spacer (An), and a poly(A) tail. A full length SVA is a ‘repeat of repeats’, composed of a CCCTCT repeat, an Alu-like domain, a GC-rich variable number of tandem repeats, and SINE-R derived from the HERV-K LTR element, followed by a poly(A) tail. It is transcribed by both RNA pol II and pol III at either internal or external promoters, and terminates similar to Alu. Finally, ERVs are transcribed by RNA pol II and encode 2–3 proteins: gag (viral core protein), pol (RT, integrase, protease) and sometimes env (viral envelope protein). ERVs are flanked by long terminal repeats (LTRs), a hallmark of their mechanism of retrotransposition. (B) Prior to reprogramming or specific cell stress, TEs are packaged into heterochromatin and their activity is suppressed, primarily through repressive DNA and histone methylation. During reprogramming, repressive marks are removed and TEs may be transcribed. A complete LINE1 element contains two coding domains, which produce ORF1 and ORF2, forming a ribonucleoprotein complex with LINE1 transcripts. Upon translocation to the nucleus, ORF2 creates a single-stranded nick in the DNA, which allows target primed reverse transcription of a new complete or partial (depicted here), LINE1 element in the genome. In contrast, SINEs only require ORF2 to replicate. Adapted from (Ostertag et al. 2003, Beck et al. 2011, Deininger 2011).

  • View in gallery

    Mechanisms of regulation by the PIWI pathway. (A) Post-transcriptional gene regulation (PTGS) of transposable elements (TE) or mRNA by piRNA-induced silencing complexes (piRISC). PiRISCs can regulate target RNA by recruiting the CAF1 deadenylation complex or through endonuclease activity and target degradation. (B) Transcriptional gene silencing is mediated by recruitment of DNA methyltransferases or chromatin components to maintain repression of TE loci.

References

  • AdelsonDLRaisonJMEdgarRC 2009 Characterization and distribution of retrotransposons and simple sequence repeats in the bovine genome. PNAS 106 1285512860. (https://doi.org/10.1073/pnas.0901282106)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AdjayeJDanielsRBoltonVMonkM 1997 cDNA libraries from single human preimplantation embryos. Genomics 46 337344. (https://doi.org/10.1006/geno.1997.5117)

  • AlmeidaLMSilvaITSilvaWAJrCastroJPRiggsPKCararetoCMAmaralMEJ 2007 The contribution of transposable elements to Bos taurus gene structure. Gene 390 180189. (https://doi.org/10.1016/j.gene.2006.10.012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AnHJLeeDLeeKHBhakJ 2004 The association of Alu repeats with the generation of potential AU-rich elements (ARE) at 3′ untranslated regions. BMC Genomics 5 97. (https://doi.org/10.1186/1471-2164-5-97)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AndersenPRTirianLVunjakMBrenneckeJ 2017 A heterochromatin-dependent transcription machinery drives piRNA expression. Nature 549 5459. (https://doi.org/10.1038/nature23482)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AravinAANaumovaNMTulinAVVaginVVRozovskyYMGvozdevVA 2001 Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Current Biology 11 10171027. (https://doi.org/10.1016/S0960-9822(01)00299-8)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AravinAGaidatzisDPfefferSLagos-QuintanaMLandgrafPIovinoNMorrisPBrownsteinMJKuramochi-MiyagawaSNakanoT 2006 A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442 203207. (https://doi.org/10.1038/nature04916)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • AravinAASachidanandamRGirardAFejes-TothKHannonGJ 2007a Developmentally regulated piRNA clusters implicate MILI in transposon control. Science 316 744747. (https://doi.org/10.1126/science.1142612)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AravinAAHannonGJBrenneckeJ 2007b The Piwi-piRNA pathway provides an adaptive defense in the transposon arms race. Science 318 761764. (https://doi.org/10.1126/science.1146484)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AravinAASachidanandamRBourc’hisDSchaeferCPezicDTothKFBestorTHannonGJ 2008 A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Molecular Cell 31 785799. (https://doi.org/10.1016/j.molcel.2008.09.003)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • AravinAAvan der HeijdenGWCastañedaJVaginVVHannonGJBortvinA 2009 Cytoplasmic compartmentalization of the fetal piRNA pathway in mice. PLoS Genetics 5 e1000764. (https://doi.org/10.1371/journal.pgen.1000764)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BarreauCPaillardLOsborneHB 2005 AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Research 33 71387150. (https://doi.org/10.1093/nar/gki1012)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BeckCRGarcia-PerezJLBadgeRMMoranJV 2011 LINE-1 elements in structural variation and disease. Annual Review of Genomics and Human Genetics 12 187215. (https://doi.org/10.1146/annurev-genom-082509-141802)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BejeranoGLoweCBAhituvNKingBSiepelASalamaSRRubinEMKentWJHausslerD 2006 A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441 8790. (https://doi.org/10.1038/nature04696)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BelancioVPRoy-EngelAMDeiningerPL 2010 All y’all need to know ‘bout retroelements in cancer. Seminars in Cancer Biology 20 200210. (https://doi.org/10.1016/j.semcancer.2010.06.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BenachenhouFJernPOjaMSperberGBlikstadVSomervuoPKaskiSBlombergJ 2009 Evolutionary conservation of orthoretroviral long terminal repeats (LTRs) and ab initio detection of single LTRs in genomic data. PLoS ONE 4 e5179. (https://doi.org/10.1371/journal.pone.0005179)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BeraldiRPittoggiCSciamannaIMatteiESpadaforaC 2006 Expression of LINE-1 retroposons is essential for murine preimplantation development. Molecular Reproduction and Development 73 279287. (https://doi.org/10.1002/mrd.20423)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BrenneckeJAravinAAStarkADusMKellisMSachidanandamRHannonGJ 2007 Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128 10891103. (https://doi.org/10.1016/j.cell.2007.01.043)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BuchanJRParkerR 2009 Eukaryotic stress granules: the ins and outs of translation. Molecular Cell 36 932941. (https://doi.org/10.1016/j.molcel.2009.11.020)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BuiLCEvsikovAVKhanDRArchillaCPeynotNHénautALe BourhisDVignonXRenardJPDuranthonV 2009 Retrotransposon expression as a defining event of genome reprogramming in fertilized and cloned bovine embryos. Reproduction 138 289299. (https://doi.org/10.1530/REP-09-0042)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • BuzdinAGogvadzeEKovalskayaEVolchkovPUstyugovaSIllarionovaAFushanAVinogradovaTSverdlovE 2003 The human genome contains many types of chimeric retrogenes generated through in vivo RNA recombination. Nucleic Acids Research 31 43854390. (https://doi.org/10.1093/nar/gkg496)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CapyPGasperiGBiémontCBazinC 2000 Stress and transposable elements: co-evolution or useful parasites? Heredity 85 101106. (https://doi.org/10.1046/j.1365-2540.2000.00751.x)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CarmellMAGirardAvan de KantHJGBourc’hisDBestorTHde RooijDGHannonGJ 2007 MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Developmental Cell 12 503514. (https://doi.org/10.1016/j.devcel.2007.03.001)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • ChenCJinJJamesDAAdams-CioabaMAParkJGGuoYTenagliaEXuCGishGMinJ 2009 Mouse Piwi interactome identifies binding mechanism of Tdrkh Tudor domain to arginine methylated Miwi. PNAS 106 2033620341. (https://doi.org/10.1073/pnas.0911640106)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • ChenCLiuJXuG 2013 Overexpression of PIWI proteins in human stage III epithelial ovarian cancer with lymph node metastasis. Cancer Biomarkers: Section A of Disease Markers 13 315321. (https://doi.org/10.3233/CBM-130360)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CoraEPandeyRRXiolJTaylorJSachidanandamRMcCarthyAAPillaiRS 2014 The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs. RNA 20 773781. (https://doi.org/10.1261/rna.044701.114)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • CoxDNChaoABakerJChangLQiaoDLinH 1998 A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes and Development 12 37153727. (https://doi.org/10.1101/gad.12.23.3715)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • CzechBHannonGJ 2016 One loop to rule them all: the ping-pong cycle and piRNA-guided silencing. Trends in Biochemical Sciences 41 324337. (https://doi.org/10.1016/j.tibs.2015.12.008)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • De FazioSBartonicekNDi GiacomoMAbreu-GoodgerCSankarAFunayaCAntonyCMoreiraPNEnrightAJO’CarrollD 2011 The endonuclease activity of Mili fuels piRNA amplification that silences LINE1 elements. Nature 480 259263. (https://doi.org/10.1038/nature10547)

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • DeiningerPL 2002 Mammalian retroelements. Genome Research 12 14551465. (https://doi.org/10.1101/gr.282402)