Abstract
The mammalian embryo undergoes a dramatic amount of epigenetic remodeling during the first week of development. In this review, we discuss several epigenetic changes that happen over the course of cleavage development, focusing on covalent marks (e.g., histone methylation and acetylation) and non-covalent remodeling (chromatin remodeling via remodeling complexes; e.g., SWI/SNF-mediated chromatin remodeling). Comparisons are also drawn between remodeling events that occur in embryos from a variety of mammalian species.
Introduction
A series of precisely timed milestones mark the first week of mammalian embryo development. Immediately after fertilization, protamines found on the DNA contributed by sperm are exchanged for histone proteins found in the oocyte cytoplasm. The process of protamine-histone exchange is the first major chromatin remodeling event experienced by the embryo. The earliest mitotic cell divisions are referred to as cleavage divisions, where duplicated DNA is divided evenly between the daughter cells without a change in overall cytoplasmic volume. In short, the cytoplasm from the fertilized oocyte is divided (or cleaved) among the newly formed embryonic cells as mitosis proceeds. The zygotic genome becomes activated at a species-specific time-point during cleavage development (during the 4-cell stage in pigs and humans, during the 2-cell stage in mice or the 8-cell stage in cattle). The embryo utilizes a pool of mRNA that was synthesized in the developing oocyte to guide the development prior to zygotic genome activation (ZGA). From the point of ZGA onward, the embryo must synthesize mRNA to direct and continue development. The first morphological differentiation takes place during the late morula stage when the embryo begins to form a blastocoel. Once the blastocoel has formed, the blastocyst stage embryo contains two cell types: The outer cells, the trophectoderm (TE), can contribute to portions of the extraembryonic membranes and placenta, while the cells of the inner cell mass (ICM) will give rise to the embryo proper.
Proper chromatin remodeling is central to successful embryo development. Chromatin remodeling enables transcription factors to access chromatin and is crucial to properly time gene activation and regulate transcription. In the mouse embryo, chromatin accessibility changes during early development. Wu et al. (2016) published a genome-wide map of accessible chromatin in early mouse embryos using a high-throughput ATAC-seq method with depletion of mitochondrial DNA. Transposable elements are highly involved in the organization of accessible chromatin. Open chromatin and cis-regulatory elements of parental genomes are reduced before major ZGA in preimplantation mouse embryos. Thereafter, there is comparable accessibility of chromatin of parental genomes. During minor ZGA, a state of largely permissive chromatin was detected (Wu et al. 2016). A computational prediction of binding sites for transcription factors (TFs) is a valuable tool to gain information about chromatin remodeling. However, information related to DNA sequence, genes or chromatin accessibility by itself is insufficient to predict global TF-binding events. Therefore, Liu et al. (2017) combined these information tools and were able to expand their program for cross-TF prediction, cross-cell type prediction and mixed prediction of TF-binding events. Genome-wide chromatin accessibility of promoter regions in human and mouse fetal germ cells can be analyzed using nucleosome occupancy and methylation sequencing. During epigenomic reprograming, nucleosome-depleted regions are found in areas of regulatory elements, especially at transcription start sites in binding regions of pluripotency-related and germ cell regulators like NANOG, SOX17, OCT4 and AP2γ, demonstrating that promoters of actively transcribed genes are highly accessible. An asymmetric spacing of nucleosomes around transcription start sites is another indicator for the involvement in the regulation of transcription (Guo et al. 2017).
With the increased use of assisted reproductive technologies (ART), the study of epigenetic changes caused by the in vitro environment has become an intense area of interest. Immense epigenetic reprogramming is occurring during preimplantation embryo development, which coincides with the period in which embryos are exposed to in vitro environment. The development of adult diseases with fetal origins (DOHaD; Developmental Origins of Health and Disease) include, but are not limited to, altered development, low birth weight, coronary disease, metabolic syndrome, large offspring syndrome, Beckwith–Wiedemann syndrome, hypertension, unbalanced fetal and placental development, anxiety and behavior disorders. Importantly, some of these disorders are passed on to subsequent generations (reviewed by Chen et al. 2015b , Ventura-Junca et al. 2015). Chen et al. (2015a) showed that ART in mice caused lower fetal birth weight and placental overgrowth, associated with hypermethylation at imprinting control regions. Dysregulated DNA methylation was also detected in bovine embryos after exposure to suboptimal culture conditions in vitro (Salilew-Wondim et al. 2015). Using porcine embryos, Canovas et al. (2017) reported aberrant transcriptome and whole genome methylation patterns in IVF blastocyst stage embryos compared to in vivo blastocysts. Some of these changes were less prominent when reproductive fluids were added during exposure of oocytes and embryos to the in vitro environment. These studies clearly demonstrate that there are negative effects on development caused by exposure to in vitro conditions, and moreover, that some of these effects could be minimized by improvements of culture conditions.
Both covalent (methylation, acetylation, phosphorylation) and non-covalent processes are involved in chromatin remodeling. Much information about chromatin remodeling has been obtained from embryonic stem (ES) cells in the mouse. While these data provide critical clues to what events occur during early embryo development and differentiation, distinct differences are found between chromatin remodeling in murine ES cells and in mammalian embryos. The current knowledge about chromatin remodeling in embryos has been derived predominantly from mouse embryos. Where available, we will discuss differences between species and influences of artificial reproductive technologies, especially exposure to in vitro environments.
Non-covalent chromatin remodeling
The DNA within eukaryotic cells is complexed around a histone octamer that consists of histone proteins H2A, H2B, H3 and H4. The histone octamer, along with its associated DNA, form the nucleosome. ATP-dependent chromatin remodeling complexes mediate changes in nucleosome spacing and alter chromatin structure to facilitate transcription factor access.
Four major classes of ATP-dependent chromatin remodeling complexes include the SWI/SNF (switch/sucrose non-fermenting, also known as BAF complexes), ISWI (imitation SWI), CHD (chromodomain helicase DNA binding) and INO80 complexes. These chromatin remodeling complexes are generally composed of multiple protein subunits, with a single catalytic subunit that uses the energy from ATP hydrolysis to reposition the underlying nucleosomes. The composition of a specific chromatin remodeling complex determines complex activity and sites of action. Unique combinations of remodeling complexes exist in various cell types.
The respective subunits that compose a given chromatin remodeling complex must gain access to a cell’s nucleus to access chromatin and mediate remodeling. Therefore, in addition to the discussion of chromatin remodeling complexes, we will review the regulatory roles nuclear trafficking receptors serve in mammalian embryos (Table 1).
ATP-dependent chromatin remodeling complexes in mammals.
| Family | Subfamily | Subunits (ATPase underlined) |
|---|---|---|
| SWI/SNF | PBAF | BRG1, BAF180, ARID2, BRD7, SNF5, BAF45A/B/C/D, BAF53A/B, BAF57, BAF60A/B/C, BAF155/170, PHF10, Actin |
| BAF-A | BRG1/BRM, ARID1A, SNF5, BAF45A/B/C/D, BAF53A/B, BAF57, BAF60A/B/C, BAF155/170, Actin, SS18, BCL7A/B/C, BCL11A/B, BRD9 | |
| esBAF | BRG1, ARID1A, SNF5, BAF45D, BAF53A, BAF57, BAF60A, BAF155, (BAF170; human), Actin, BCL7A/B/C | |
| BAF-B | BRG1/BRM, ARID1B, SNF5, BAF45A/B/C/D, BAF53A/B, BAF57, BAF60A/B/C, BAF155/170, Actin, SS18, BCL7A/B/C, BCL11A/B, BRD9 | |
| ISWI | ACF | SNF2H, ACF1 |
| CHRAC | SNF2H, ACF1, CHRAC15/17 | |
| NoRC | SNF2H, TIP5 | |
| WICH | SNF2H, WSTF | |
| RSF | SNF2H/L, RSF1 | |
| NURF | SNF2L, BPTF, RBAP46/48 | |
| CERF | SNF2H/L, CECR2 | |
| CHD | CHD | CHD1/2/6-9 |
| NuRD | CHD3/4, HDAC1/2, MTA1/2/3, RBAP46/48, GATAD2 A/B, MBD2/3 | |
| NuRD-like | CHD5, HDAC2, GATAD2 B, MTA3, RBAP46 | |
| INO80/SWR | INO80 | INO80, RUVBL1/2, MCRS1, AMIDA, BAF53A, YY1, IES6/2, UCH37, NFRKB, INO80E |
| SRCAP | SRCAP, RUVBL1/2, GAS41, BAF53, D<AP1, YL-1, ARP6, ZnF-HIT1 | |
| P400/TIP60 | p400, RUVBL1/2, TRRAP, Tip60, BRD8, BAF53, EPC1/2, YL-1, GAS41, DMAP1, ING3, FLJ11730, MRG15, MRGX, MRGBP |
SWI/SNF
SWI/SNF complexes (also referred to as BAF complexes) disassemble nucleosomes, thereby creating stretches of DNA that provide open access for transcription factors. Previous studies have shown that SWI/SNF chromatin remodeling complexes are composed of multiple subunits, and their composition varies depending on cell type and developmental stage (Kadoch et al. 2013). All BAF complexes contain a central remodeling core that includes the following four subunits: BAF150, BAF170, SNF5 and a core ATPase. BRM (SMARCA2) or BRG1 (SMARCA4) function as the ATPase in all SWI/SNF complexes (Ryme et al. 2009, Euskirchen et al. 2012).
There are at least 29 genes from 15 gene families encoding these subunits (Kadoch & Crabtree 2015). SWI/SNF complexes have been associated with tumor suppression; mutation or loss of function of various individual subunits of the SWI/SNF complex have been identified to be involved in several cancers in human (Reisman et al. 2009, Kadoch & Crabtree 2015, Marquez-Vilendrer 2016). Several unique SWI/SNF complexes have been identified in different cell types. Examples of these complexes include esBAF (found in embryonic stem cells), nBAF (found in neurons) and pnBAF (found in neural progenitor cells). Further studies will most likely reveal the existence of additional complexes with unique combinations of BAF subunits.
Embryonic stem (ES) cells are derived from the inner cell mass (ICM) of preimplantation embryos. They retain their undifferentiated state when cultured and propagated in vitro, have the potential for self-renewal and can differentiate into cells derived from all 3 germ layers. esBAF complexes are essential for ES cell self-renewal and pluripotency (Ho et al. 2009). esBAF complexes have been defined by the presence of BRG1 as the ATPase, BAF155 as the scaffolding subunit, and BAF60A, as well as the absence of BRM, BAF170 and BAF60C. A recent study, however, showed that while BRG1 is predominantly found in esBAF complexes, BRM is able to compensate for BRG1 to some extent (Smith-Roe & Bultman 2013). In contrast to findings in mice, Zhang et al. (2014) detected the presence of both BAF155 and BAF170, as well as BAF53A in addition to BRG1 and ARID1A in human ES cells.
Knockout studies in mice have shown varying developmental requirements for discrete SWI/SNF subunits (Table 2). While Brm-null mice survive to adulthood and show only a slight overgrowth phenotype (Reyes et al. 1998), Brg1-null mice are lethal at embryonic stages (Bultman et al. 2000). Brg1 has been shown to be expressed during early embryo development, while Brm appears to be associated with later development and differentiation (Ryme et al. 2009). Gene inactivation of Snf5 or Baf155 results in peri-implantation lethality, and BAF180-null mice show lethality at E12.2-E15.5 due to cardiac and placenta abnormalities (reviewed by de la Serna et al. 2006, Xu et al. 2012). Panamarova et al. (2016) demonstrated that Baf155 knockdown in mice resulted in aberrant expression of pluripotency genes, while overexpression of Baf155 caused developmental arrest at the blastocyst stage. Similar to the mouse, BRG1 transcripts are present from the pronuclear to blastocyst stage in cleavage stage porcine preimplantation embryos. In contrast, BRM transcripts are readily detectable in GV-stage porcine oocytes, but their abundance decreases significantly as development proceeds to the blastocyst stage (Magnani & Cabot 2007).
Knockout studies in mice.
| Family | Gene | KO effect | Reference |
|---|---|---|---|
| SWI/SNF | Brm | Slight overgrowth | Reyes et al. (1998) |
| Brg1 | Embryonic lethal | Bultman et al. (2000) | |
| Snf5 | Peri-implantation lethal | Reviewed by de la Serna et al. (2006) | |
| Baf57 | Early embryonic lethal | Reviewed by Lessard & Crabtree (2010) | |
| Arid1a | Arrest around E 6.5 | Gao et al. (2008) | |
| Arid1b | Normal blastocyst development | Yan et al. (2008) | |
| Baf155 | Peri-implantation lethal, aberrant expression of pluripotency genes | Reviewed by de la Serna et al. (2006), Panamarova et al. (2016) | |
| Baf180 | Lethal E12.2-E15.5 | Xu et al. (2012) | |
| CHD/NuRD | Cdh1 | Post-implantation lethal | Suzuki et al. (2015) |
| Chd1l | Developmental arrest before blastocyst | Snider et al. (2013) | |
| Mta2 | Partial embryonic and peri-natal lethal | Lu et al. (2008) | |
| Mbd3 | Abnormal epiblast, no ICM maturation | Kaji et al. (2007) | |
| ISWI/NURF | Snf2h | Peri-implantation lethal | Stopka & Skoultchi, (2003) |
| Snf2l | Survive, normal reproduction | Yip et al. (2002) | |
| Bpft | Post-implantation lethal | Landry et al. (2008) | |
| INO80 | Ino80 | Reduced blastocyst development | Wang et al. (2014) |
Differences in localization and abundance of several SWI/SNF subunits between in vitro- and in vivo-produced porcine embryos have been detected. Additionally, there are distinct differences to what has been reported in murine embryos and ES cells. Similar to data reported in murine ES cells, BAF155 protein adopts clear nuclear localization in early cleavage stage porcine embryos, which then decreases by the blastocyst stage. Unlike data reported in murine ES cells, but similar to findings in human ES cells (Zhang et al. 2014), BAF170 is detectable at most stages of embryo development. Interestingly, it appears that porcine blastocyst stage embryos produced by in vitro fertilization show a stronger preference for BAF170 compared to ex vivo blastocysts (Cabot et al. 2017). This is especially surprising since embryos produced in vitro generally develop slower than in vivo–derived embryos (reviewed by Lazzari et al. 2010).
Arid1a has been reported to be ubiquitously expressed in all regions and stages in cleavage stage murine embryos, while Arid1b is first detectable at the 8 cell stage of development (Flores-Alcantar et al. 2011). Similar to data in mice, ARID1A is present in GV-stage porcine oocytes and cleavage stage embryos (pronuclear to blastocyst stage) in both in vitro and in vivo–derived embryos. ARID1B is not detectable in GV-stage oocytes or pronuclear and 4-cell stage porcine embryos. ARID1B is detected in the majority of blastocyst stage embryos produced by in vitro fertilization, while only a small percentage of ex vivo blastocyst stage embryos reveals the presence of ARID2 (Cabot et al. 2017) together with Baf180 (Pbrm1, polybromo protein 1) and Brd7, are signature subunits for the PBAF (polybromo BAF) complex, which has been shown to be critical for mouse embryo development. Embryonic lethality is observed in Baf180-null mice (Xu et al. 2012). Data in porcine embryos reveal different intracellular locations of BAF180, ARID2 and BRD7 as compared to what has been reported in mice. In addition to very weak or undetectable staining signals reflecting BAF180, also differences between ARID2 and BRD7 staining have been detected. ARID2 shows nuclear localization throughout porcine preimplantation embryo development, while BRD7 reveals a clear cytoplasmic staining pattern in 4-cell and blastocyst stage embryos (both in vitro-produced and in vivo–derived embryos; Fig. 1), indicating that classic PBAF complexes do not exist in early porcine embryos (Cabot et al. 2017).
CHD (chromodomain helicase DNA/binding)
Members of the CHD chromatin remodeling complexes are characterized by two N-terminal chromodomains, the centrally located helicase ATPase domain, and a C-terminal DNA/binding domain. There are three known subfamilies of CHD complexes with limited homology, each of them including several different CHD complexes (subfamily I: CHD1 and CHD2; subfamily II: CHD3 and CHD4, NuRD (nucleosome remodeling and histone deacetylation) complexes; subfamily III: CHD5-9, Kismet-L, bib4D-14, and KIAA1416). While members of subfamily I have clear DNA-binding domains, those of subfamily II seem to exhibit their DNA binding activity through a double N-terminal PHD zincfinger and members of subfamily III contain a SANT domain which acts as the DNA-binding domain (reviewed by Hall & Goergel 2007). Complexes of CHD subfamily 3 are formed between CHD7, PARP1 and PBAF (Witkowski & Foulkes 2015), which clearly demonstrates that chromatin remodeling is a very complex event with overlapping functions of different systems. Another organization of CHD complexes is the classification into CHD and NuRD (Nucleosome Remodeling and Deacetylase) complexes (Table 1), depending on the number of subunits (CHD:1 subunit, NuRD: multiple subunits) (reviewed by Zhang et al. 2016).
NuRD complexes can bind methylated DNA, which subsequently leads to deacetylation of DNA-methylated nucleosomes (Feng & Zhang 2003). NuRD complexes act as transcriptional co-repressors. Chromodomain helicase DNA-binding protein 3 (CHD3), a core subunit of the NuRD complex, colocalizes with HDAC1, MTA3 and H3K9ac and binds to histone H3 tails via their PHD fingers. With increased hydrophobicity – mediated by methylation (H3K9me3) or acetylation (H3K9ac) – this binding of PHD fingers to histone H3 gets enhanced, which in turn loosens interactions of histone H3 tails within nucleosomes and promotes nucleosome unwrapping (Tencer et al. 2017).
Mta2 (Metastasis Tumor Antigen 2), a component of NuRD complexes, exhibits dramatically increased levels during zygotic genome activation, and has been shown to be involved in the regulation of DNA methylation and expression of maternally expressed genes in preimplantation mouse embryos (Ma et al. 2010). Targeted mutation of the Mta2 gene also results in partial embryonic and perinatal lethality in mice (Lu et al. 2008). Mbd3, a core component of NuRD co-repressor complexes, is required for embryo development. In mice, Mbd3-null embryos show abnormal epiblast expansion and trophectoderm development starting at E5.5, ICM cells fail to mature after implantation. The authors also demonstrate that Mbd3 is essential for proper gene expression in murine embryos pre- and peri-implantation (Kaji et al. 2007).
In mouse blastocysts, Chd1l is expressed predominantly in the ICM. Antisense morpholino injections result in developmental arrest before the blastocyst stage. The requirement for Chd1l in murine preimplantation development is especially interesting, since Chd1l has been found to be non-essential for ES cell survival (Snider et al. 2013). In bovine embryos, Zhang et al. (2016) found that CHD1 protein regulates histone variant H3.3 deposition, and CHD1 levels increase after meiotic maturation, stay elevated after fertilization and subsequently decrease rapidly. siRNA injections result in reduced development to the morula and blastocyst stage. Interestingly, however, expression of marker genes for ICM (NANOG) and trophectoderm (CDX2) are not affected.
Interactions with other chromatin remodeling complexes and covalent chromatin remodeling systems, as well as reported mutant mouse models (Marfella et al. 2006, Kaji et al. 2007, Lu et al. 2008) strongly indicate that CHD complexes are another crucial factor in the complex chromatin remodeling processes occurring during early mammalian embryo development.
ISWI (imitation SWI)
ISWI chromatin remodeling complexes disrupt interactions between histones and DNA and thereby enable nucleosome movement along the chromatin. There are seven different ISWI complexes (ACF – ATP-utilizing chromatin assembly and remodeling factor, CHRAC – chromatin accessibility complex, NoRC – nucleolar remodeling complex, WICH – WSTF-ISWI chromatin remodeling complex, RSF – remodeling and spacing factor, NURF – nucleosome remodeling factor, CERF). ISWI complexes contain either SNF2H or SNF2L as their ATPase. NURF complexes seem to be associated with activation of transcription, CHRAC complexes have been found to deactivate transcription. Stopka & Skoultchi (2003) found that SNF2H is required for early embryo development in the mouse. While Snf2h heterozygous embryos develop to term, Snf2h − / − embryos die around implantation. At day E3.5, Snf2h − / − embryos appear normal, however, no embryos can be detected by E7.5 indicating peri-implantation lethality. SNF2H colocalizes with BRG1 and TIF (Transcription Intermediary factor) 1α, indicating an interaction of ISWI and SWI/SNF complexes that affects and/or regulates transcription. Ablation of TIF1α in mouse embryos causes developmental arrest at the 2-4-cell stage. In addition, an aberrant localization of BRG1 and SNF2H indicates that TIF1α might be a factor influencing nuclear localization of chromatin remodeling ATPases (Torres-Padilla & Zernicka-Goetz 2006).
Another study in early embryos revealed that Bpft (bromodomain PDH/finger transcription factor), which is the largest of the NURF complex subunits, is essential for embryo development in the mouse. Homozygous Bpft-knockout mice implant properly. However, Bpft depletion results in post-implantation lethality starting at E7.5; by E8.5 the majority of embryos are reabsorbed (Landry et al. 2008). The authors concluded that Bpft most likely is not required for preimplantation development. They did, however, address the possibility that maternal Bpft protein or Bpft mRNA could mask preimplantation phenotypes.
INO80 family (SWI/SNF-related (SWR))
In mammals, the INO80 family consists of 3 distinct complexes: INO80, SRCAP and p400/TIP60 (Witkowski & Foulkes 2015). SCRAP and p400/TIP60 complexes make up the SWR subfamily (Table 1). The remodeling ATPase, Ino80, of the INO80 subfamily facilitates an accessible chromatin architecture at pluripotency genes and is associated with gene activation (Wang et al. 2014). INO80/SWR remodeling complexes control histone H2A.Z variant exchange to nucleosomes that contain H2A and are required for ES cell differentiation (Creyghton et al. 2008, Subramanian et al. 2013). While most chromatin remodelers translocate mainly along DNA at the H3–H4 interface of nucleosomes, INO80 has been shown to act along the interface of H2A.Z-H2B dimers (Brahma et al. 2017). Wang et al. (2014) suggest that INO80 is required for the expression of pluripotency factors in ES cells and may directly regulate it. During embryo development in mice, Ino80 expression increases consistently up to the blastocyst stage, where it is expressed in nuclei of ICM cells. Knockdown of Ino80 results in significantly reduced blastocyst formation as well as reduced expression of pluripotency genes (Wang et al. 2014), further confirming an important role of INO80 complexes in early embryo development, most likely due to regulation of proper expression of pluripotency genes.
An extensive review of ATP-dependent chromatin remodeling during post-implantation development and differentiation can be found in Hota & Bruneau 2016.
Other important complexes affecting transcription are the Polycomb Repressive Complexes (PRCs). They are composed of Polycomb group (PcG) proteins which are important for forming and maintaining a repressive state of the chromatin. PRCs are targeted to specific genes, e.g. via DNA binding proteins or non-coding RNAs, and mediate chromatin modifications like methylation of H3K27, which result in repression of transcription (Leeb et al. 2010).
Covalent chromatin remodeling
Covalent modifications of chromatin impact the interaction between histones and DNA and influence the ability of transcription machinery to interact with a given genomic locus. These epigenetic marks have been characterized in a variety of model systems. In addition to DNA methylation, a multitude of covalent histone modifications are known to exist and have been studied in mammalian cells, including methylation, acetylation, ubiquitination, and sumoylation. There are several reviews available that discuss epigenetic remodeling (Reik et al. 2001, Marcho et al. 2015, Ross & Cavovas 2016; among others). We limit this review to exemplary findings pertaining methylation and acetylation of histone tails in cleavage stage embryos.
Histone methylation
Histone methylation can be associated with either gene activation or repression, depending on which amino acid residue is modified, and to what degree it is methylated (i.e., mono-, di- or tri-methylation). For instance, trimethylation of the lysine 27 residue of histone H3 (H3K27me3) is associated with gene silencing, while mono- and trimethylation of the lysine 4 residue of histone H3 (H3K4me3 and H3K4me1, respectively) are indicators for expressed genes or active enhancers (Ross & Canovas 2016). While reprogramming during fertilization removes most epigenetic marks, regions for imprinting control are excluded from this reprograming.
Maternally and paternally inherited chromatin can possess differential histone methylation patterns. In pronuclear stage mouse embryos, dimethylated and trimethylated lysine residues on histone proteins H3 and H4 (including H3K9 and H3K27) are only detectable on maternally derived chromatin (Lepikhov & Walter 2004). The male pronucleus in murine embryos does not possess dimethylation or trimethylation on H3K9, but it does possess monomethylated H3K9 and H3K27 (Santos et al. 2005). Monomethylated H3K4 (H3K4me1) is present on paternally-derived chromatin in the male pronucleus in mouse embryos; H3K4me1 is required for minor zygotic genome activation in mouse embryos (Aoshima et al. 2015). Lepikov et al. (2008) detected conserved patterns of histone H3K9 methylation in pronuclear stage bovine, murine, and leporine embryos, in which an asymmetric distribution of H3K9 dimethylation (H3K9me2) is present. In these species, maternally derived chromatin possesses H3K9me2, while paternally-derived chromatin does not.
While the mouse is a critical model for mammalian embryo biology, there are differences in histone methylation patterns between mammalian species (Beaujean et al. 2004, Yang et al. 2007). Dimethylated H3K9 has been reported to differentially mark the chromatin in male and female pronuclei in murine embryos (Lui et al. 2004), where maternally derived chromatin contains H3K9me2 and paternally derived chromatin lacks H3K9me2. Lui and colleagues proposed that the presence of H3K9me2 protected maternally derived DNA from active DNA demethylation that is observed to occur to paternally-derived DNA at the pronuclear stage. In contrast, there is an assymetric distribution of H3K9me2 in porcine embryos at the pronuclear stage, but this asymmetry does not strictly demarcate male and female pronuclei (Sega et al. 2007).
Trimethylated H3K36 has been found to be present exclusively in the maternal pronucleus of mouse zygotes that is then dramatically reduced by the two-cell stage (Boskovic et al. 2012). Low levels of H3K36me3 become detectable in murine 4-cell stage embryos and further increase up to the 8-cell stage. A heterogeneous distribution of H3K36me3 is detected in blastocyst stage embryos with not all nuclei being positive for H3K36me3 (Boskovic et al. 2012). In bovine embryos, however, H3K36me3 is mostly undetectable at the pronuclear stage. H3K36me3 shows a heterogeneous pattern between the 4- to 8-cell stages in which some nuclei are positive for H3K36me3; this heterogeneous pattern persists to the blastocyst stage (Boskovic et al. 2012).
The highest levels of trimethylated H3K27 (H3K27me3) have been observed in oocytes in cattle, mice, and pigs. H3K27me3 adopts an asymmetric localization in pronuclear stage embryos (H3K27me3 is found on only maternally derived chromatin), followed by a gradual decrease in this epigenetic mark up to the point of zygotic genome activation, with a subsequent increase in H3K27me3 at the blastocyst stage in bovine embryos (Bogliotti & Ross 2012). Pig embryos display a similar pattern to that found in bovine embryos, where a gradual reduction of H3K27me3 is found as embryos proceed through cleavage development (Park et al. 2009, Gao et al. 2010), with a reappearance of H3K27me3 evident at the hatched blastocyst stage (Gao et al. 2010). In mice, H3K27me3 is retained up to the morula stage, at which point a decrease of H3K27me3 is observed. This decrease is followed by an increase of H3K27me3 in the ICM of blastocyst stage embryos, while the trophectoderm remains hypomethylated (Dahl et al. 2010, Bogliotti & Ross 2012). In contrast, Inoue et al. (2017) found maternal allele-specific trimethylated H3K27 associated with 76 paternally expressed genes in preimplantation embryos. Ectopic removal of H3K27me3 induces maternal expression of these genes, indicating a DNA methylation independent mechanism of imprinting. After differentiation, H3K27me3 dependent imprinting is largely lost in the embryonic lineage; in contrast, it is maintained in the extraembryonic lineage (Inoue et al. 2017).
Herrmann et al. (2013) used bovine in vitro-produced blastocyst stage embryos to analyze the expression of developmentally critical genes and their relation of histone H3 modifications (H3K4me3 and H3K9ac as marks of transcriptionally active promotors and H3K27me3 and K3K9me3 as repressive modifications, respectively). ChIP analysis revealed promotor occupancy of H3K4me3 and K3K9ac for active states of promotors, and conversely low levels of H3K27me3 and H3K9me3 promotor occupancy for repressed genes. For example, NANOG is expressed at higher levels in ICM compared to the trophectoderm (TE) cells. Accordingly, there is a higher occupancy of H3K4me3 and H3K9ac on the NANOG promotor in ICM cells compared to TE. The opposite situation has been detected for H3K27me3 and H3K9me3.
Histone acetylation
Histone acetylation marks are obtained through the action of a variety of histone acetyl transferases (HATs), and are removed by histone deacetylases (HDACs). In general, histone acetylation neutralizes the charge of lysine residues and has been associated with a relaxed chromatin state. This relaxed state is generally considered permissive for transcription.
Neither sperm nor oocyte chromatin exhibits hyperacetylated histones. Basic protamines on paternal chromosomes are progressively exchanged to histone proteins during sperm decondensation shortly after the sperm enters the oocytes. At this time, the paternal chromatin becomes highly acetylated at histone H4, which facilitates incorporation of the histone. Hyperacetylation of H4 in both male and female pronuclei reach equivalent levels in mouse embryos as S-phase begins (Adenot et al. 1997).
Studies in mouse embryos revealed that there is a transient exclusive location of acetylated lysine 64 on histone H3 (H3K64ac) in the male pronucleus in early zygotes, followed by the presence of equivalent levels of H3K64ac in both male and female pronuclei in later zygotes. H3K64ac remains detectable, albeit at low levels, throughout preimplantation development up to the blastocyst stage. This pattern seems to oppose the trimethylation pattern on the same position (H3K64me3). H3K64me3 is present in the maternal pronucleus and later becomes largely undetectable from the late two-cell stage onward (Ziegler-Birling et al. 2016). The same study shows that acetylation of the lysine 122 residue of histone H3 (H3K122ac) is present in only very low levels in early murine embryos with an increase in staining intensity at the blastocyst stage. Another acetylated lysine residue, lysine 56, on histone H3 (H3K56ac), is abundant in all preimplantation stages from the late pronuclear stage onward. The authors did not detect differences in the location of H3K64ac, H3K122ac, or H3K56ac between cells of the inner cell mass and trophectoderm in mouse embryos (Ziegler-Birling et al. 2016).
Boskovic et al. (2012) investigated dynamic changes of the acetylation patterns of the histone variant 2A.Z (H2A.Zac) near its N-terminus at the lysines residues at positions K4, K7, and K11, and acetylation at the lysine 9 residue of histone H3 (H3K9ac) in murine and bovine preimplantation embryos. Significant species-specific and stage-specific differences have been observed (Table 3). While in mouse embryos, low levels of acetylated H2A.Zac are detected in both pronuclei of zygotes, no signal can be detected at the two-cell stage, indicating an uncoupling from zygotic genome activation. From the four-cell stage onward, H2A.Z is found to be highly acetylated throughout preimplantation development. No obvious differences in acetylation levels are detected between the cells of the inner cell mass and trophectoderm. In bovine embryos, H2A.Zac is detected almost exclusively in the maternal pronucleus and in nuclei of cells at all other stages of embryo development through the blastocyst stage. Maalouf et al. (2008) analyzed histone H4 acetylation at lysine residues K5, K8, K12, and K16 in bovine preimplantation embryos produced by in vitro fertilization. Both pronuclei are transiently hyperacetylated, with the male pronucleus undergoing faster acetylation. The authors also showed an inverse correlation between histone acetylation and DNA methylation. Acetylation at K5 and K12 decreases from the one- to two-cell stage, followed by a gradual increase in acetylation. The highest level of acetylation is found at the 8 cell stage which coincides with zygotic genome activation in bovine embryos. At the blastocyst stage, high levels of acetylation are present in the trophectoderm. In contrast, cells of the inner cell mass show very little acetylation. This pattern is also observed for lysine residues K8 and K16 of histone H4, albeit more subtle.
Covalent histone modifications.
| Histone/lysine residue | Modification | Preimplantation development/function | Species | Reference |
|---|---|---|---|---|
| H3K4 | me3 | Expressed genes, active enhancers, Blastocyst: high levels in ICM | Bovine | Herrman et al. (2013), Ross and Canovas (2016), Ziegler-Birling et al. (2016) |
| H3K9 | me1 | Male PN | Murine | Santos et al. (2005) |
| H3K9 | me2/me3 | Female PN | Murine, bovine, leporine | Lepikhov and Walter (2004) |
| H3K9 | me2 | Both PN | Porcine | Sega et al. (2007) |
| H3K27 | me1 | Male PN | murine | Santos et al. (2005) |
| H3K27 | me3 | Repressed genes, silencing Female PN | Murine, bovine, leporine | Ross and Canovas (2016), Lepikhov and Walter (2004) |
| Retained levels to morula, then decrease, blastocyst: present in ICM only | murine | Dahl et al. (2010), Bogliotti and Ross (2012) | ||
| Only female PN, decrease until ZGA, then increase to blastocyst; low in ICM | Bovine, porcine | Bogliotti and Ross (2012), Park et al. (2009), Gao et al. (2010) | ||
| H3K36 | me3 | Female PN, decrease to ZGA, then increase to 8-cell, blastocyst: heterogenous | murine | Boscovic et al. (2012) |
| Undetectable in PN, heterogeneous from 4-cell to blastocyst | bovine | Boscovic et al. (2012) | ||
| H364 | me3 | Female PN, undetectable from 2-cell onward | murine | Ziegler-Birling et al. (2016) |
| Ac | Both PN, low levels up to blastocyst | Ziegler-Birling et al. (2016) | ||
| H3K56 | Ac | Abundant late PN onward | Murine | Ziegler-Birling et al. (2016) |
| H3K122 | Ac | Low levels early, increase at blastocyst | Murine | Ziegler-Birling et al. (2016) |
| H2A.ZK4/7/11 | Ac | Low in PN, absent at ZGA, increase from 4-cell on | Murine | Boskovic et al. (2012) |
| Female PN and all stages of preimplantation development | Bovine | Boskovic et al. (2012) | ||
| H4K5/8/12/16 | Ac | Both PN hyperacetylated, decrease at 2-cell, then gradual increase, peak at ZGA, blastocyst: high in TE | Maalouf et al. (2008) |
ICM, inner cell mass; PN, pronuclear stage; TE, trophectoderm; ZGA, zygotic genome activation.
Nuclear trafficking
Changes in epigenetic states, both covalent chromatin modifications and non-covalent chromatin remodeling processes, are generally mediated by intracellular factors that must access the nucleus to impart a change in the epigenetic state of chromatin. Several nuclear trafficking pathways have been identified in mammalian cells, each pathway consists of a cohort of transport factors that target discrete intracellular cargoes (e.g., proteins, mRNA), interact with the nuclear pore complexes embedded within the nuclear envelope, and move the cargo to the appropriate intracellular compartment.
Intracellular localization of BRD7, ARID2 and BAF180 in 4-cell stage porcine embryos. PBAF complex components ARID2, BRD7 and BAF180 adopt unique intracellular localization patterns in 4-cell stage porcine embryos. ARID2 is found in both nuclear and cytoplasmic compartments at the 4-cell stage, while BRD7 is detectable only in the cytoplasm; BAF180 is not detectable at this stage of development.
Citation: Reproduction 155, 3; 10.1530/REP-17-0488
Nuclear import
Nuclear import mediated by the karyopherin α/β heterodimer is one of the best-characterized nuclear trafficking systems (Gorlich & Kutay 1999). Karyopherin α (KPNA) interacts with a nuclear localization signal (NLS) found in the primary amino acid sequence of import substrates. NLSs recognized by KPNA typically consist of small clusters of basic amino acids. The monpartite NLS is typified by the NLS found in the SV40-T antigen (-PKKKRKV-), while the bipartite NLS is exemplified by the NLS found in nucleoplasmin (-KRPAATKKAGQAKKK-; Reichelt et al. 1990). Once bound to its cargo, KPNA binds to karyopherin β (KPNB) and the trimeric complex translocates through the nuclear pore complex (Gorlich et al. 1996). The trimeric complex disassociates in the nucleus upon binding to the GTPase Ran (Ribbeck et al. 1998). A schematic representation of karyopherin α/β mediated nuclear import is illustrated in Fig. 2.
Schematic model of karyopherin α/β mediated nuclear import. A Karyopherin α (KPNA) subtype (i.e., KPNA1-KPNA7) recognizes intracellular cytoplasmic proteins that bear a nuclear localization signal (NLS). KPNA associates with karyopherin β (KPNB) once KPNA has bound to the NLS-bearing cargo. The trimeric complex then associates with components of the nuclear pore complex, translocates to the nucleus and then disassociates upon interacting with the GTPase, Ran.
Citation: Reproduction 155, 3; 10.1530/REP-17-0488
Seven karyopherin α subtypes have been characterized in mammals, these include karyopherin α1-α7 (KPNA1-KPNA7; Cabot & Prather 2003, Tejomurtula et al. 2009, Kelley et al. 2010, Hu et al. 2010, Wang et al. 2012). It has been shown previously that each of the KPNA subtypes shares a high degree of sequence identity (50–80%) (Kamei et al. 1999) and each subtype transports proteins bearing an NLS. It appears that certain NLS-bearing proteins are preferentially imported by specific KPNA subtypes. The proteins Ran binding protein 3 (RANBP3) and RCC1 have an increased affinity for KPNA3 (Welch et al. 1999, Talcott & Moore 2000). KPNA2 and KPNA1 have different binding affinities for a variety of NLSs in vitro (Kohler et al. 1999). In addition, karyopherin α subtypes show tissue-specific expression patterns. Kpna3 and Kpna4 have been detected only in the Leydig cells of the testes, while Kpna1, Kpna5, and Kpna6 have been found in all cells of the testes (Kamei et al. 1999). KPNA7 appears to be an ovary and embryo-specific karyopherin α subtype, in that it has been detected in cDNA derived from ovarian tissue, oocytes, and cleavage stage embryos (Tejomurtula et al. 2009, Wang et al. 2012).
KPNA developmental requirements
The most compelling data to indicate a lack of complete functional redundance between individual KPNA subtypes comes from studies involving Kpna knockout mice. Kpna1 (also referred to as importin α 5) knock out mice are viable and show no apparent developmental phenotype, although Kpna1 has been previously implicated in neural differentiation (Shmidt et al. 2007). In contrast, Kpna6 null mice (also referred to as importin α 7) are viable, null females, however, ovulate oocytes that are not capable of supporting embryo development beyond the 2-cell stage (Rother et al. 2011). Kpna7 null mice are viable, but these mice display reduced fertility and fecundity. There appears to be a skewed sex ratio where a higher proportion of female than male conceptuses are reabsorbed (Hu et al. 2010).
KPNA cargo specificity – a link to SWI/SNF chromatin remodeling
A series of protein:protein interaction screens have been conducted with the goal of identifying cargoes trafficked by individual KPNA subtypes (Park et al. 2012, Hugel et al. 2014). Kpna6 null mice reveal a very clear reproductive phenotype, therefore identifying the cargoes trafficked specifically by Kpna6 could help elucidate the pathways that are perturbed in Kpna6 null animals; these screens reveal multiple NLS-bearing putative KPNA cargoes. Of particular interest is a small group of chromatin remodeling factors, including Brg1. Although Brg1 still adopts a nuclear localization in oocytes derived from Kpna6 null animals, the amount of Brg1 in the nucleus is reduced (Hugel et al. 2014). Considering that multiple Brg1 associated factors complex with Brg1 to form functional chromatin remodeling complexes, it is possible that the fraction of Brg1, or perhaps a subset of discrete Brg1 associated factors, is unable to enter the nucleus in the absence of Kpna6, thereby leading to alterations in key chromatin remodeling activities that occur in immature oocytes arrested in meiosis. Although KPNA6 transcripts are detectable at equivalent levels from GV-stage oocyte to blastocyst stage porcine embryo (Wang et al. 2012), KPNA6 is detectable as a nuclear protein in the GV-stage oocyte. KPNA6 is enriched in the cytoplasm in cleavage stage embryos through the blastocyst stage of development, suggesting that the cargoes KPNA6 transports exert their roles in the oocyte rather than in the cleavage stage embryo (Cabot, unpublished findings).
It has also been shown that the transcription factor Brn2 (a transcription factor involved in neural differentiation with a known NLS; Yasuhara et al. 2007) interacts with all KPNA subtypes but has a significantly higher binding affinity for KPNA7 in vitro (Li et al. 2015). Recombinant, fluorescently labeled Brn2 adopts a nuclear localization when injected into porcine oocytes and embryos up to the 4-cell stage of development. However, at the 8-cell stage Brn2 adopts a nuclear localization in only a subset of blastomeres. Although the possibility that protein stability contributed to this unique finding cannot be ruled out, it is important to note that KPNA7, the KPNA subtype that Brn2 exhibited the highest binding affinity, begins to decrease transcript abundance after the 4-cell stage and is not detected as a nuclear protein beyond the 4-cell stage.
In conclusion, chromatin remodeling is a complex process that is facilitated by a multitude of different systems. There are differences between species, and more importantly, it has been found, that these systems are susceptible to environmental influences like in vitro conditions and assisted reproductive technologies. We are only beginning to understand the scope of effects that aberrant chromatin remodeling has on the developing embryo, on the health and development beyond birth into adulthood, as well as subsequent generations.
Declaration of interest
The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This project was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award number R01HD084309.
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