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Protamines: lessons learned from mouse models

Lena Arévalo, Gina Esther Merges, Simon Schneider, and Hubert Schorle

In brief

Protamines package and shield the paternal DNA in the sperm nucleus and have been studied in many mouse models over decades. This review recapitulates and updates our knowledge about protamines and reveals a surprising complexity in protamine function and their interactions with other sperm nuclear proteins.

Abstract

The packaging and safeguarding of paternal DNA in the sperm cell nucleus is a critical feature of proper sperm function. Histones cannot mediate the necessary hypercondensation and shielding of chromatin required for motility and transit through the reproductive tracts. Paternal chromatin is therefore reorganized and ultimately packaged by protamines. In most mammalian species, one protamine is present in mature sperm (PRM1). In rodents and primates among others, however, mature sperm contain a second protamine (PRM2). Unlike PRM1, PRM2 is cleaved at its N-terminal end. Although protamines have been studied for decades due to their role in chromatin hypercondensation and involvement in male infertility, key aspects of their function are still unclear. This review updates and integrates our knowledge of protamines and their function based on lessons learned from mouse models and starts to answer open questions. The combined insights from recent work reveal that indeed both protamines are crucial for the production of functional sperm and indicate that the two protamines perform distinct functions beyond simple DNA compaction. Loss of one allele of PRM1 leads to subfertility whereas heterozygous loss of PRM2 does not. Unprocessed PRM2 seems to play a distinct role related to the eviction of intermediate DNA-bound proteins and the incorporation of both protamines into chromatin. For PRM1, on the other hand, heterozygous loss leads to strongly reduced sperm motility as the main phenotype, indicating that PRM1 might be important for processes ensuring correct motility, apart from DNA compaction.

DOI:
https://doi.org/10.1530/REP-22-0107
Volume 164: Issue 3,
Pages:
R57–R74
Restricted access

The reduction of oocytes and disruption of the meiotic prophase I in Fanconi anemia E-deficient mice

Huan Yin, Suye Suye, Zhixian Zhou, Haiyi Cai, and Chun Fu

In brief

Fanconi anemia results in subfertility and primary ovarian deficiency in females. This study reveals that disrupted meiosis in oocytes is one of the mechanisms involved.

Abstract

Fance is an important factor participating in the repair of DNA interstrand cross-links and its defect causes severe follicle depletion in female mice. To explore the underlying mechanisms, we investigated the effects of Fance on ovarian development in embryonic and newborn mice. We found that the number of oocytes was significantly decreased in Fance −/− mice as early as 13.5 days post coitum (dpc). The continuous decrease of oocytes in Fance −/− mice compared with the Fance +/+ mice led to the primordial follicles being almost exhausted at 2 days postpartum (dpp). The mitotic–meiotic transition occurred normally, but the meiotic progression was arrested in pachytene in Fance −/− oocytes. We detected the expressions of RAD51 (homologous recombination repair factor), 53BP1 (non-homologous end-joining repair factor), and γH2AX by immunostaining analysis and chromosome spreads. The expressions of 53BP1 were increased and RAD51 decreased significantly in Fance −/− oocytes compared with Fance +/+ oocytes. Also, the meiotic crossover indicated by MLH1 foci was significantly increased in Fance −/− oocytes. Oocyte proliferation and apoptosis were comparable between Fance −/− and Fance +/+ mice (P > 0.05). The aberrant high expression at 17.5 dpc and low expressions at 1 and 2 dpp indicated that the expression pattern of pluripotent marker OCT4 (POU5F1) was disordered in Fance −/− oocytes. These findings elucidate that Fance mutation leads to a progressive reduction of oocytes and disrupts the progression of meiotic prophase I but not the initiation. And, our study reveals that the potential mechanisms involve DNA damage repair, meiotic crossover, and pluripotency of oocytes.

DOI:
https://doi.org/10.1530/REP-21-0421
Volume 164: Issue 3,
Pages:
71–82 (12 total)
Restricted access

Early growth response 1 transcription factor is essential for the pathogenic properties of human endometriotic epithelial cells

Vineet K Maurya, Maria M Szwarc, Rodrigo Fernandez-Valdivia, David M Lonard, Song Yong, Niraj Joshi, Asgerally T Fazleabas, and John P Lydon

Although a non-malignant gynecological disorder, endometriosis displays some pathogenic features of malignancy, such as cell proliferation, migration, invasion and adaptation to hypoxia. Current treatments of endometriosis include pharmacotherapy and/or surgery, which are of limited efficacy and often associated with adverse side effects. Therefore, to develop more effective therapies to treat this disease, a broader understanding of the underlying molecular mechanisms that underpin endometriosis needs to be attained. Using immortalized human endometriotic epithelial and stromal cell lines, we demonstrate that the early growth response 1 (EGR1) transcription factor is essential for cell proliferation, migration and invasion, which represent some of the pathogenic properties of endometriotic cells. Genome-wide transcriptomics identified an EGR1-dependent transcriptome in human endometriotic epithelial cells that potentially encodes a diverse spectrum of proteins that are known to be involved in tissue pathologies. To underscore the utility of this transcriptomic data set, we demonstrate that carbonic anhydrase 9 (CA9), a homeostatic regulator of intracellular pH, is not only a molecular target of EGR1 but is also important for maintaining many of the cellular properties of human endometriotic epithelial cells that are also ascribed to EGR1. Considering therapeutic intervention strategies are actively being developed for EGR1 and CAIX in the treatment of other pathologies, we believe EGR1 and its transcriptome (which includes CA9) will offer not only a new conceptual framework to advance our understanding of endometriosis but will also furnish new molecular vulnerabilities to be leveraged as potential therapeutic options in the future treatment of endometriosis.

DOI:
https://doi.org/10.1530/REP-22-0123
Volume 164: Issue 2,
Pages:
41–54 (14 total)
Free access

The immunobiology of preterm labor and birth: intra-amniotic inflammation or breakdown of maternal–fetal homeostasis

Nardhy Gomez-Lopez, Jose Galaz, Derek Miller, Marcelo Farias-Jofre, Zhenjie Liu, Marcia Arenas-Hernandez, Valeria Garcia-Flores, Zachary Shaffer, Jonathan M Greenberg, Kevin R Theis, and Roberto Romero

In brief

The syndrome of preterm labor comprises multiple established and novel etiologies. This review summarizes the distinct immune mechanisms implicated in preterm labor and birth and highlights potential strategies for its prevention.

Abstract

Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, results from preterm labor, a syndrome that includes multiple etiologies. In this review, we have summarized the immune mechanisms implicated in intra-amniotic inflammation, the best-characterized cause of preterm labor and birth, as well as novel etiologies non-associated with intra-amniotic inflammation (i.e. formally known as idiopathic). While the intra-amniotic inflammatory responses driven by microbes (infection) or alarmins (sterile) have some overlap in the participating cellular and molecular processes, the distinct natures of these two conditions necessitate the implementation of specific approaches to prevent adverse pregnancy and neonatal outcomes. Intra-amniotic infection can be treated with the correct antibiotics, whereas sterile intra-amniotic inflammation could potentially be treated by administering a combination of anti-inflammatory drugs (e.g. betamethasone, inflammasome inhibitors, etc.). Recent evidence also supports the role of fetal T-cell activation as a newly described trigger for preterm labor and birth in a subset of cases diagnosed as idiopathic. Moreover, herein we also provide evidence of two maternally-driven immune mechanisms responsible for preterm births formerly considered to be idiopathic. First, the impairment of maternal Tregs can lead to preterm birth, likely due to the loss of immunosuppressive activity resulting in unleashed effector T-cell responses. Secondly, homeostatic macrophages were shown to be essential for maintaining pregnancy and promoting fetal development, and the adoptive transfer of homeostatic M2-polarized macrophages shows great promise for preventing inflammation-induced preterm birth. Collectively, in this review, we discuss the established and novel immune mechanisms responsible for preterm birth and highlight the potential targets for novel strategies aimed at preventing the multi-etiological syndrome of preterm labor leading to preterm birth.

DOI:
https://doi.org/10.1530/REP-22-0046
Volume 164: Issue 2,
Pages:
R11–R45
Restricted access

Involvement of the linker histone H1Foo in the regulation of oogenesis

Satoshi Funaya, Yuria Kawabata, Kenta Sugie, Ken-ichiro Abe, Yutaka Suzuki, Masataka G Suzuki, and Fugaku Aoki

In brief

In oocytes, chromatin structure is loosened during their growth, which seems to be essential for the establishment of competence to accomplish the maturation and further development after fertilization. This paper shows that a linker histone variant, H1foo, is involved in the formation of loosened chromatin structure in growing oocytes.

Abstract

During oogenesis, oocytes show a unique mode of division and gene expression patterns. Chromatin structure is thought to be involved in the regulation of these processes. In this study, we investigated the functions of linker histones, which modulate higher-order chromatin structure during oogenesis. Because H1foo is highly expressed in oocytes, we knocked down H1foo using siRNA and observed oocyte growth, maturation, and fertilization. However, H1foo knockdown had no effect on any of these processes. Overexpression of H1b or H1d, which has a high ability to condense chromatin and is expressed at a low level in oocytes, resulting in tightened chromatin and a decreased success rate of oocyte maturation. By contrast, overexpression of H1a, which is expressed at a high level in oocytes and has a low ability to compact chromatin, did not affect growth or maturation. Therefore, H1a, but not other variants, might compensate for the function of H1foo in H1foo-knockdown oocytes. These results implicate H1foo in the formation of loose chromatin structure, which is necessary for oocyte maturation. In addition, the low expression of somatic linker histone variants, for example, H1b and H1d, is important for loosened chromatin and meiotic progression.

DOI:
https://doi.org/10.1530/REP-21-0233
Volume 164: Issue 2,
Pages:
19–29 (11 total)
Restricted access

The nuclear receptors SF1 and COUP-TFII cooperate on the Insl3 promoter in Leydig cells

Mickaël Di-Luoffo, Kenley Joule Pierre, Nicholas M Robert, Marie-Joëlle Girard, and Jacques J Tremblay

In brief

The insulin-like 3 (INSL3) hormone produced by Leydig cells is essential for proper male sex differentiation, but the regulation of Insl3 expression remains poorly understood. This study describes a new physical and functional cooperation between the nuclear receptors SF1 and COUP-TFII in Insl3 expression.

Abstract

INSL3, a hormone abundantly produced by Leydig cells, is essential for testis descent during fetal life and bone metabolism in adults. The mechanisms regulating Insl3 expression in Leydig cells have been studied in several species but remain poorly understood. To date, only a handful of transcription factors are known to activate the Insl3 promoter and include the nuclear receptors AR, NUR77, COUP-TFII, and SF1, as well as the Krüppel-like factor KLF6. Some of these transcription factors are known to transcriptionally cooperate on the Insl3 promoter, but the mechanisms at play remain unknown. Here, we report that COUP-TFII and SF1 functionally cooperate on the Insl3 promoter from various species but not on the Inha, Akr1c14, Cyp17a1, Hsd3b1, Star, Gsta3, and Amhr2 promoters that are known to be regulated by COUP-TFII and/or SF1. The Insl3 promoter contains species-conserved binding sites for COUP-TFII (−91 bp) and SF1 (−134 bp). Mutation of either the COUP-TFII or the SF1 sequence had no impact on the COUP-TFII/SF1 cooperation, but the mutation of both binding sites abolished the cooperation. In agreement with this, we found that COUP-TFII and SF1 physically interact in Leydig cells. Finally, we report that the transcriptional cooperation is not limited to COUP-TFII and SF1 as it also occurred between all NR2F and NR5A family members. Our data provide new mechanistic insights into the cooperation between the orphan nuclear receptors COUP-TFII and SF1 in the regulation of Insl3 gene expression in Leydig cells.

DOI:
https://doi.org/10.1530/REP-22-0109
Volume 164: Issue 2,
Pages:
31–40 (10 total)
Free access

Quantitative aspects of estrogen metabolism in mammalian female and male reproductive systems

James I Raeside

Although the role of estrogens in the development and function of tissues in the reproductive and other systems has long been recognized, their relative concentrations in target tissues have received scant attention. In this regard, the significance of local metabolism of estrogens is clearly shown by incubation of tissues with radiolabeled estrogens.

DOI:
https://doi.org/10.1530/REP-22-0188
Volume 164: Issue 2,
Pages:
V1–V3
Open access

Single-cell transcriptomics of staged oocytes and somatic cells reveal novel regulators of follicle activation

Yu-Ying Chen, Daniela D Russo, Riley S Drake, Francesca E Duncan, Alex K Shalek, Brittany A Goods, and Teresa K Woodruff

In brief

Proper development of ovarian follicles, comprised of an oocyte and surrounding somatic cells, is essential to support female fertility and endocrine health. Here, we describe a method to isolate single oocytes and somatic cells from the earliest stage follicles, called primordial follicles, and we characterize signals that drive their activation.

Abstract

Primordial follicles are the first class of follicles formed in the mammalian ovary and are comprised of an oocyte surrounded by a layer of squamous pre-granulosa cells. This developmental class remains in a non-growing state until individual follicles activate to initiate folliculogenesis. What regulates the timing of follicle activation and the upstream signals that govern these processes are major unanswered questions in ovarian biology. This is partly due to the paucity of data on staged follicle cells since isolating and manipulating individual oocytes and somatic cells from early follicle stages are challenging. To date, most studies on isolated primordial follicles have been conducted on cells collected from animal-age- or oocyte size-specific samples, which encompass multiple follicular stages. Here, we report a method for collecting primordial follicles and their associated oocytes and somatic cells from neonatal murine ovaries using liberase, DNase I, and Accutase. This methodology allows for the identification and collection of follicles immediately post-activation enabling unprecedented interrogation of the primordial-to-primary follicle transition. Molecular profiling by single-cell RNA sequencing revealed that processes including organelle disassembly and cadherin binding were enriched in oocytes and somatic cells as they transitioned from primordial to the primary follicle stage. Furthermore, targets including WNT4, TGFB1, FOXO3, and a network of transcription factors were identified in the transitioning oocytes and somatic cells as potential upstream regulators that collectively may drive follicle activation. Taken together, we have developed a more precise characterization and selection method for studying staged-follicle cells, revealing several novel regulators of early folliculogenesis.

DOI:
https://doi.org/10.1530/REP-22-0053
Volume 164: Issue 2,
Pages:
55–70 (16 total)
Restricted access

Follicular free fatty acid metabolic signatures and their effects on oocyte competence in non-obese PCOS patients

Yifan Feng, Jia Qi, Xinli Xue, Xinyu Li, Yu Liao, Yun Sun, Yongzhen Tao, Huiyong Yin, Wei Liu, Shengxian Li, and Rong Huang

In Brief

Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility in women. This study identified changes in free fatty acids profiles in the follicular fluid that may lead to better diagnosis and management of infertility in PCOS women.

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous disease characterized by various endocrine/metabolic disorders and impaired reproductive potential. Alterations in oocyte competence are considered potentially causative factors for infertility in PCOS women and analyzing the composition of follicular fluid in these patients may help to identify which changes have the potential to alter oocyte quality. In this study, free fatty acid metabolic signatures in follicular fluid were performed to identify changes that may impact oocyte competence in non-obese PCOS women. Sixty-four non-obese women (32 with PCOS and 32 age- and BMI-matched controls) undergoing in vitro fertilization were recruited. Embryo quality was morphologically assessed. Free fatty acid metabolic profiling in follicular fluid was performed using gas/liquid chromatography-mass spectrometry. Principal component analysis and orthogonal partial least squares-discriminant analysis models were further constructed. Nine free fatty acids and 24 eicosanoids were identified and several eicosanoids synthesized by the cyclooxygenase pathway were significantly elevated in PCOS patients compared to controls. The combination of PGE2, PGF2α, PGJ2, and TXB2 had an area under the curve of 0.867 (0.775–0.960) for PCOS discrimination. Furthermore, follicular fluid levels of PGE2 and PGJ2 were negatively correlated with high-quality embryo rate in PCOS patients (P < 0.05). Metabolomic analysis revealed that follicular fluid lipidomic profiles undergo changes in non-obese PCOS women, which suggests that identifying changes in important metabolic signatures may give us a better understanding of the pathogenesis of PCOS. Furthermore, elevated PGE2 and PGJ2 concentrations may contribute to impaired oocyte competence in non-obese PCOS patients.

DOI:
https://doi.org/10.1530/REP-22-0023
Volume 164: Issue 1,
Pages:
1–8 (8 total)
Free access

Irisin and the fibronectin type III domain-containing family: structure, signaling and role in female reproduction

Mathilde Daudon, Yves Bigot, Joëlle Dupont, and Christopher A Price

In Brief

Hormones secreted by muscle cells (myokines) are involved in the adaptive response to nutritional and metabolic changes. In this review, we discuss how one family of myokines may alter fertility in response to sudden changes in energy balance.

Abtract

Dietary stress such as obesity and short-term changes in energy balance can disrupt ovarian function leading to infertility. Adipose tissue secretes hormones (adipokines), such as leptin and adiponectin, that are known to alter ovarian function. Muscles can also secrete endocrine factors, and one such family of myokines, the eleven Fibronectin type III domain-containing (FNDC) proteins, is emerging as important for energy sensing and homeostasis. In this review, we summarize the known roles the FNDC proteins play in energy homeostasis and explore potential impacts on fertility in females. The most well-known member, FNDC5, is the precursor of the ‘exercise hormone’, irisin, secreted by both muscle and adipose tissue. The receptors for irisin are integrins, and it has recently been shown to alter steroidogenesis in ovarian granulosa cells although the effects appear to be species or context specific, and irisin may improve uterine and placental function in women and rodent models. Another member, FNDC4, is also cleaved to release a bioactive protein that modulates insulin sensitivity in peripheral tissues and whose receptor, ADGRF5, is expressed in the ovary. As obese women and farm animals in negative energy balance (NEB) both have altered insulin sensitivity, secreted FNDC4 may impact ovarian function. We propose a model in which NEB or dietary imbalance alters plasma irisin and secreted FNDC4 concentrations, which then act on the ovary through their cognate receptors to reduce granulosa cell proliferation and follicle health. Research into these molecules will increase our understanding of energy sensing and fertility and may lead to new approaches to alleviate post-partum infertility.

DOI:
https://doi.org/10.1530/REP-22-0037
Volume 164: Issue 1,
Pages:
R1–R9