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Frontiers in Cell and Developmental... 2021Meiosis is the basis of sexual reproduction. In female mammals, meiosis of oocytes starts before birth and sustains at the dictyate stage of meiotic prophase I before... (Review)
Review
Meiosis is the basis of sexual reproduction. In female mammals, meiosis of oocytes starts before birth and sustains at the dictyate stage of meiotic prophase I before gonadotropins-induced ovulation happens. Once meiosis gets started, the oocytes undergo the leptotene, zygotene, and pachytene stages, and then arrest at the dictyate stage. During each estrus cycle in mammals, or menstrual cycle in humans, a small portion of oocytes within preovulatory follicles may resume meiosis. It is crucial for females to supply high quality mature oocytes for sustaining fertility, which is generally achieved by fine-tuning oocyte meiotic arrest and resumption progression. Anything that disturbs the process may result in failure of oogenesis and seriously affect both the fertility and the health of females. Therefore, uncovering the regulatory network of oocyte meiosis progression illuminates not only how the foundations of mammalian reproduction are laid, but how mis-regulation of these steps result in infertility. In order to provide an overview of the recently uncovered cellular and molecular mechanism during oocyte maturation, especially epigenetic modification, the progress of the regulatory network of oocyte meiosis progression including meiosis arrest and meiosis resumption induced by gonadotropins is summarized. Then, advances in the epigenetic aspects, such as histone acetylation, phosphorylation, methylation, glycosylation, ubiquitination, and SUMOylation related to the quality of oocyte maturation are reviewed.
PubMed: 33842483
DOI: 10.3389/fcell.2021.654028 -
Nature Communications Jun 2023In mammals, the production of mature oocytes necessitates rigorous regulation of the discontinuous meiotic cell-cycle progression at both the transcriptional and...
In mammals, the production of mature oocytes necessitates rigorous regulation of the discontinuous meiotic cell-cycle progression at both the transcriptional and post-transcriptional levels. However, the factors underlying this sophisticated but explicit process remain largely unclear. Here we characterize the function of N-acetyltransferase 10 (Nat10), a writer for N4-acetylcytidine (ac4C) on RNA molecules, in mouse oocyte development. We provide genetic evidence that Nat10 is essential for oocyte meiotic prophase I progression, oocyte growth and maturation by sculpting the maternal transcriptome through timely degradation of poly(A) tail mRNAs. This is achieved through the ac4C deposition on the key CCR4-NOT complex transcripts. Importantly, we devise a method for examining the poly(A) tail length (PAT), termed Hairpin Adaptor-poly(A) tail length (HA-PAT), which outperforms conventional methods in terms of cost, sensitivity, and efficiency. In summary, these findings provide genetic evidence that unveils the indispensable role of maternal Nat10 in oocyte development.
Topics: Animals; Mice; Mammals; Meiosis; Oocytes; Oogenesis; RNA, Messenger
PubMed: 37349316
DOI: 10.1038/s41467-023-39256-0 -
Cell Reports Mar 2022The DSB machinery, which induces the programmed DNA double-strand breaks (DSBs) in the leptotene and zygotene stages during meiosis, is suppressed before the onset of...
The DSB machinery, which induces the programmed DNA double-strand breaks (DSBs) in the leptotene and zygotene stages during meiosis, is suppressed before the onset of the pachytene stage. However, the biological significance and underlying mechanisms remain largely unclear. Here, we report that ZFP541 is indispensable for the suppression of DSB formation after mid-pachytene. The deletion of Zfp541 in mice causes the aberrant recruitment of DSB machinery to chromosome axes and generation of massive DSBs in late pachytene and diplotene spermatocytes, leading to meiotic arrest at the diplotene stage. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data indicate that ZFP541 predominantly binds to promoters of pre-pachytene genes, including meiotic DSB formation-related genes (e.g., Prdm9 and Mei1) and their upstream activators (e.g., Meiosin and Rxra), and maintains their repression in pachytene spermatocytes. Our results reveal that ZFP541 functions as a transcriptional regulator in pachytene spermatocytes, orchestrating the transcriptome to ensure meiosis progression.
Topics: Animals; Chromosomal Proteins, Non-Histone; DNA Breaks, Double-Stranded; Histone-Lysine N-Methyltransferase; Male; Meiosis; Meiotic Prophase I; Mice; Pachytene Stage; Spermatocytes; Transcription Factors
PubMed: 35320728
DOI: 10.1016/j.celrep.2022.110540 -
Nucleic Acids Research Oct 2022Post-transcriptional RNA modifications critically regulate various biological processes. N4-acetylcytidine (ac4C) is an epi-transcriptome, which is highly conserved in...
Post-transcriptional RNA modifications critically regulate various biological processes. N4-acetylcytidine (ac4C) is an epi-transcriptome, which is highly conserved in all species. However, the in vivo physiological functions and regulatory mechanisms of ac4C remain poorly understood, particularly in mammals. In this study, we demonstrate that the only known ac4C writer, N-acetyltransferase 10 (NAT10), plays an essential role in male reproduction. We identified the occurrence of ac4C in the mRNAs of mouse tissues and showed that ac4C undergoes dynamic changes during spermatogenesis. Germ cell-specific ablation of Nat10 severely inhibits meiotic entry and leads to defects in homologous chromosome synapsis, meiotic recombination and repair of DNA double-strand breaks during meiosis. Transcriptomic profiling revealed dysregulation of functional genes in meiotic prophase I after Nat10 deletion. These findings highlight the crucial physiological functions of ac4C modifications in male spermatogenesis and expand our understanding of its role in the regulation of specific physiological processes in vivo.
Topics: Male; Mice; Animals; Meiosis; Cytidine; Chromosome Pairing; Germ Cells; Mammals
PubMed: 35801907
DOI: 10.1093/nar/gkac594 -
ELife Jul 2023Impaired spermatogenesis and male infertility are common manifestations associated with mitochondrial diseases, yet the underlying mechanisms linking these conditions...
Impaired spermatogenesis and male infertility are common manifestations associated with mitochondrial diseases, yet the underlying mechanisms linking these conditions remain elusive. In this study, we demonstrate that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of the mitochondrial encephalopathy Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis during meiotic prophase I, followed by degeneration and death of arrested spermatocytes. This process is independent of neurodegeneration. Interestingly, genetic modifications of PINK1, PGAM5, and TTC19 - three major substrates of PARL with important roles in mitochondrial homeostasis - fail to reproduce or modify this severe phenotype, indicating that the spermatogenic arrest arises from distinct molecular pathways. We further observed severe abnormalities in mitochondrial ultrastructure in PARL-deficient spermatocytes, along with prominent electron transfer chain defects, disrupted coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ cell-specific decrease in GPX4 expression leading arrested spermatocytes to ferroptosis - a regulated cell death modality characterized by uncontrolled lipid peroxidation. Our results suggest that mitochondrial defects induced by PARL depletion act as an initiating trigger for ferroptosis in primary spermatocytes through simultaneous effects on GPX4 and CoQ - two major inhibitors of ferroptosis. These findings shed new light on the potential role of ferroptosis in the pathogenesis of mitochondrial diseases and male infertility warranting further investigation.
Topics: Animals; Humans; Male; Mice; Ferroptosis; Infertility, Male; Meiosis; Metalloproteases; Mitochondrial Proteins; Spermatogenesis
PubMed: 37505079
DOI: 10.7554/eLife.84710 -
Nucleic Acids Research Aug 2023DNA-RNA hybrids play various roles in many physiological progresses, but how this chromatin structure is dynamically regulated during spermatogenesis remains largely...
DNA-RNA hybrids play various roles in many physiological progresses, but how this chromatin structure is dynamically regulated during spermatogenesis remains largely unknown. Here, we show that germ cell-specific knockout of Rnaseh1, a specialized enzyme that degrades the RNA within DNA-RNA hybrids, impairs spermatogenesis and causes male infertility. Notably, Rnaseh1 knockout results in incomplete DNA repair and meiotic prophase I arrest. These defects arise from the altered RAD51 and DMC1 recruitment in zygotene spermatocytes. Furthermore, single-molecule experiments show that RNase H1 promotes recombinase recruitment to DNA by degrading RNA within DNA-RNA hybrids and allows nucleoprotein filaments formation. Overall, we uncover a function of RNase H1 in meiotic recombination, during which it processes DNA-RNA hybrids and facilitates recombinase recruitment.
Topics: Humans; Male; Cell Cycle Proteins; DNA; Meiosis; Rad51 Recombinase; Recombinases; Spermatocytes; Ribonuclease H
PubMed: 37378420
DOI: 10.1093/nar/gkad524 -
Biology of Reproduction Jun 2020
Topics: Animals; Cell Cycle Checkpoints; Cell Cycle Proteins; Humans; Male; Meiosis; Meiotic Prophase I; Metaphase; SKP Cullin F-Box Protein Ligases; Spermatozoa; Ubiquitin
PubMed: 32338765
DOI: 10.1093/biolre/ioaa063 -
Frontiers in Cell and Developmental... 2021Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia.... (Review)
Review
Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1-5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20-25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women.
PubMed: 33763429
DOI: 10.3389/fcell.2021.652407 -
Genes & Development Feb 2022Mechanisms regulating meiotic progression in mammals are poorly understood. The -methyladenosine (mA) reader and 3' → 5' RNA helicase YTHDC2 switches cells from...
Mechanisms regulating meiotic progression in mammals are poorly understood. The -methyladenosine (mA) reader and 3' → 5' RNA helicase YTHDC2 switches cells from mitotic to meiotic gene expression programs and is essential for meiotic entry, but how this critical cell fate change is accomplished is unknown. Here, we provide insight into its mechanism and implicate YTHDC2 in having a broad role in gene regulation during multiple meiotic stages. Unexpectedly, mutation of the mA-binding pocket of YTHDC2 had no detectable effect on gametogenesis and mouse fertility, suggesting that YTHDC2 function is mA-independent. Supporting this conclusion, CLIP data defined YTHDC2-binding sites on mRNA as U-rich and UG-rich motif-containing regions within 3' UTRs and coding sequences, distinct from the sites that contain mA during spermatogenesis. Complete loss of YTHDC2 during meiotic entry did not substantially alter translation of its mRNA binding targets in whole-testis ribosome profiling assays but did modestly affect their steady-state levels. Mutation of the ATPase motif in the helicase domain of YTHDC2 did not affect meiotic entry, but it blocked meiotic prophase I progression, causing sterility. Our findings inform a model in which YTHDC2 binds transcripts independent of mA status and regulates gene expression during multiple stages of meiosis by distinct mechanisms.
Topics: Animals; Gene Expression Regulation; Male; Mammals; Meiosis; Mice; RNA Helicases; RNA, Messenger; Spermatogenesis
PubMed: 35058317
DOI: 10.1101/gad.349190.121 -
Molecular Reproduction and Development Sep 2022During oogenesis, oocytes arrest at meiotic prophase I to acquire competencies for resuming meiosis, fertilization, and early embryonic development. Following this... (Review)
Review
During oogenesis, oocytes arrest at meiotic prophase I to acquire competencies for resuming meiosis, fertilization, and early embryonic development. Following this arrested period, oocytes resume meiosis in response to species-specific hormones, a process known as oocyte maturation, that precedes ovulation and fertilization. Involvement of endocrine and autocrine/paracrine factors and signaling events during maintenance of prophase I arrest, and resumption of meiosis is an area of active research. Studies in vertebrate and invertebrate model organisms have delineated the molecular determinants and signaling pathways that regulate oocyte maturation. Cell cycle regulators, such as cyclin-dependent kinase (CDK1), polo-like kinase (PLK1), Wee1/Myt1 kinase, and the phosphatase CDC25 play conserved roles during meiotic resumption. Extracellular signal-regulated kinase (ERK), on the other hand, while activated during oocyte maturation in all species, regulates both species-specific, as well as conserved events among different organisms. In this review, we synthesize the general signaling mechanisms and focus on conserved and distinct functions of ERK signaling pathway during oocyte maturation in mammals, non-mammalian vertebrates, and invertebrates such as Drosophila and Caenorhabditis elegans.
Topics: Animals; Caenorhabditis elegans; Cyclin-Dependent Kinases; Drosophila; Drosophila Proteins; Extracellular Signal-Regulated MAP Kinases; Female; Hormones; Mammals; Meiosis; Oocytes; Oogenesis; Phosphoric Monoester Hydrolases; Protein Kinases; Signal Transduction
PubMed: 35908193
DOI: 10.1002/mrd.23637