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Argonaute proteins regulate the timing of the spermatogenic transcriptional program [miRNA-seq]

ABSTRACT: Argonaute proteins are known for their role in microRNA-mediated post-transcriptional gene silencing. Using a triple Ago413-/- mouse model, we show that AGO3 and AGO4 are key regulators of spermatogenesis, orchestrating expression of meiosis-related genes during prophase I, while maintaining silencing of spermiogenesis genes. Overexpression of spermiogenesis genes during prophase I in Ago413-/- mice results in subfertility. Here, we show that AGO3, but not AGO2, localizes to the sex chromatin of pachytene spermatocytes, where together with AGO4, it is required for transcriptional silencing of XY-linked genes. We also identify BRG1, a BAF complex subunit as an AGO3 interactor, and observe that loss of AGO3 and AGO4 leads to increased BRG1 in spermatocytes, evidencing a role for AGO3 in transcriptional control during meiosis. Notably, we reveal that altered gene regulation during prophase I given by loss of AGO3 and AGO4 transcends the meiotic phase of spermatogenesis, leading to poor quality germ cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE284040 | GEO | 2026/06/22

REPOSITORIES: GEO

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Argonaute proteins regulate the timing of the spermatogenic transcriptional program [scRNA-seq]

Project description:Argonaute proteins are known for their role in microRNA-mediated post-transcriptional gene silencing. Using a triple Ago413-/- mouse model, we show that AGO3 and AGO4 are key regulators of spermatogenesis, orchestrating expression of meiosis-related genes during prophase I, while maintaining silencing of spermiogenesis genes. Overexpression of spermiogenesis genes during prophase I in Ago413-/- mice results in subfertility. Here, we show that AGO3, but not AGO2, localizes to the sex chromatin of pachytene spermatocytes, where together with AGO4, it is required for transcriptional silencing of XY-linked genes. We also identify BRG1, a BAF complex subunit as an AGO3 interactor, and observe that loss of AGO3 and AGO4 leads to increased BRG1 in spermatocytes, evidencing a role for AGO3 in transcriptional control during meiosis. Notably, we reveal that altered gene regulation during prophase I given by loss of AGO3 and AGO4 transcends the meiotic phase of spermatogenesis, leading to poor quality germ cells.

2026-06-22 | GSE284038 | GEO

Argonaute proteins regulate the timing of the spermatogenic transcriptional program [RNA-seq]

2026-06-22 | GSE284037 | GEO

Argonaute proteins orchestrate Meiotic Sex Chromosome Inactivation and timing of the spermatogenic transcriptional program [Multiome]

Project description:Argonaute proteins (AGO) are best known for their role in microRNA-mediated post-transcriptional gene silencing. Here, we demonstrate that AGO3 and AGO4, but not AGO2, localize to the sex chromatin of pachytene spermatocytes, where they are required for the transcriptional silencing of XY-linked genes that characterizes Meiotic Sex Chromosome Inactivation (MSCI). Previous findings showed that deletion of Ago4 (Ago4-/-) mildly impairs MSCI and normal spermatozoa production. By contrast, loss of Ago3 (Ago3-/-) does not produce these defects, while combined deletion of Ago1, Ago3, and Ago4 (Ago413-/-) leads to severely reduced fertility, accompanied by disrupted autosomal and sex chromosome gene regulation and altered chromatin accessibility in spermatocytes. In Ago413-/- mice, premature overexpression of spermiogenesis genes during prophase I results in reduced sperm production, abnormal sperm morphology, and impaired fertilization capacity. Together, AGO3 and AGO4 act during prophase I to ensure the timely expression of meiosis-related genes during prophase I while maintaining repression of spermiogenesis-associated genes. These results indicate that AGO3 and AGO4 act in a coordinated fashion in the male germline to orchestrate cell progression in spermatogenesis through temporal regulation of autosomal and sex chromosome genes.

2026-06-22 | GSE332917 | GEO

AGO4 Regulates Entry into Meiosis and Influences Silencing of Sex Chromosomes in the Male Mouse Germline

Project description:The four mammalian Argonaute family members are thought to share redundant functions in the microRNA pathway, yet only AGO2 possesses the catalytic "slicer" function required for RNA interference. Whether AGO1, AGO3, or AGO4 possess specialized functions remains unclear. Here, we Series_summary = show that AGO4 localizes to spermatocyte nuclei during meiotic prophase I, specifically at sites of asynapsis and in the transcriptionally silenced XY sub-domain, the sex body. We generated Ago4 knockout mice and show that Ago4-/- spermatogonia initiate meiosis early, resulting from premature induction of retinoic acid-response genes. During prophase I, the sex body assembles incorrectly in Ago4-/- mice, leading to disrupted meiotic sex chromosome inactivation (MSCI). This is associated with a dramatic loss of microRNAs, >20% of which arise from the X chromosome. Loss of AGO4 results in increased AGO3 in spermatocytes, indicating some degree of redundancy. Thus, AGO4 regulates meiotic entry and MSCI in mammalian germ cells, implicating small RNA pathways in these processes. mRNA transcripts were isolated and prepared using pachytene spermatocytes, pre-meiotic testes and other tissues from Ago4+/+ and Ago4-/- littermates and sequenced using Illumina HiSeq2000. small RNA transcripts were isolated and prepared using pachytene spermatocytes from adult Ago4+/+ and Ago4-/- littermates and sequenced using Illumina GAII.

2012-08-01 | E-GEOD-39652 | biostudies-arrayexpress

AGO4 Regulates Entry into Meiosis and Influences Silencing of Sex Chromosomes in the Male Mouse Germline

2012-08-01 | GSE39652 | GEO

TOPBP1 Shapes XY Silencing Dynamics Independently of Sex Body Formation to Ensure Male Fertility

Project description:In mammals and several other taxa, the ability of males to cope with the limited synapsis of the X and Y chromosomes during prophase I of meiosis relies on the process of meiotic sex chromosome inactivation (MSCI). Components of the somatic DNA damage response machinery, including ATR, TOPBP1, MDC1 and BRCA1 play key roles in MSCI, although how they establish XY silencing remains incompletely understood. In particular, it remains unclear how DDR factors coordinate XY silencing with DNA repair, chromosome synapsis and the formation of the sex body, a distinct phase-separated sub-nuclear structure formed during prophase I to house the unsynapsed XY bivalent. Here we report a mutant mouse (Topbp1B5/B5), harboring mutations in the BRCT5 domain of Topbp1, that shows impaired XY silencing but grossly normal sex body formation. While Topbp1B5/B5 mice are viable, without detectable somatic defects, males are completely infertile. Distinct from mice lacking ATR or TOPBP1 specifically during meiosis, Topbp1B5/B5 males exhibit normal chromosome synapsis and canonical markers of DNA repair in early prophase I. ATR signaling is mostly intact in Topbp1B5/B5 spermatocytes, although specific ATR-dependent events are disrupted, including localization of the RNA:DNA helicase Senataxin to chromatin loops of the XY. Strikingly, while Topbp1B5/B5 spermatocytes are able to initiate MSCI the completion of gene silencing is defective, with a subset of X chromosome genes displaying distinct patterns of transcriptional deregulation. These findings suggest a non-canonical role for the ATR-TOPBP1 signaling axis in XY silencing dynamics at advanced stages in pachynema. This is the first DDR mutant that separates XY silencing from sex body formation, as well as TOPBP1’s role in spermatogenesis from its roles in organismal viability.

2024-02-09 | PXD042199 | Pride

Screening of genes involved in chromosome segregation in meiosis I

Project description:Prophase I of male meiosis involves dynamic chromosome segregation processes during early spermatogenesis, including synapsis, meiotic recombination, and cohesion. Genetic defects in genes participating in these processes consistently cause reproduction failure in mice. To identify candidate genes responsible for infertility in humans, we performed expression profiling of mouse spermatogenic cells undergoing meiotic prophase I. Cell fractions enriched in spermatogonia, leptotene/zygotene spermatocytes, or pachytene spermatocytes were separately isolated from mouse testes for RNA extraction. To minimize the contamination of other cell types, we fractionated the testicular cells undergoing the first round of spermatogenesis using Percoll gradient procedure. The cell fractions were characterized by morphological analysis by phase contrast microscopy and Nomarski interference microscopy, and then expression of cell lineage- and spermatogenesis stage-specific genes were examined by RT-PCR. The most enriched fractions for spermatogonia (fraction2 from day8), leptotene/zygotene spermatocytes (fraction5 from day12), and pachytene spermatocytes (fraction8 from day15) were subjected to hybridization on Affymetrix microarrays.

2010-03-31 | E-GEOD-19532 | biostudies-arrayexpress

Transcription profiling of mouse germline during spermatogenesis reveals X and Y occupy a novel compartment in the post-meiotic spermatid and adopt a non-Rabl configuration

Project description:In mammals, the X and Y chromosomes are subject to meiotic sex chromosome inactivation (MSCI) during prophase I in the male germline, but their status thereafter is currently unclear. An abundance of X-linked spermatogenesis genes has spawned the view that the X must be active [1-8]. On the other hand, the idea that the imprinted paternal X of the early embryo may be pre-inactivated by MSCI suggests that silencing may persist longer [9-12]. To clarify this issue, we establish a comprehensive X-expression profile during mouse spermatogenesis. Here, we discover that the X and Y occupy a novel compartment in the post-meiotic spermatid and adopt a non-Rabl configuration. We demonstrate that this post-meiotic sex chromatin (PMSC) persists throughout spermiogenesis into mature sperm and exhibits epigenetic similarity to the XY body. In the spermatid, 87% of X-linked genes remain suppressed post-meiotically, while autosomes are largely active. We conclude that chromosome-wide X-silencing continues from meiosis to the end of spermiogenesis and discuss implications for proposed mechanisms of imprinted X-inactivation. Independent germ cell preps were used for array analysis. Duplicates were provided for each sample.

2007-12-07 | E-GEOD-4193 | biostudies-arrayexpress

Phosphoproteome of mouse testis

Project description:Spermatogenesis is a complex sperm-generating process involving the mitosis of spermatogonia, meiosis of spermatocytes and spermiogenesis of spermatids. Elucidating the phosphorylation-based regulations should advance our understanding of the underlying molecular mechanisms. Here we present an integrative study of phosphorylation events in the testis. Large-scale phosphoproteome profiling in the adult mouse testis identified 17,829 phosphorylation sites in 3,955 phosphoproteins.

2014-10-10 | PXD000767 | Pride

ISWI chromatin remodeler SMARCA5 is essential for meiotic gene expression and male fertility in mammals

Project description:Regulation of the transcriptome to promote meiosis is important for sperm development and fertility. However, how chromatin remodeling directs the transcriptome during meiosis in male germ cells is largely unknown. Here, we demonstrate that the ISWI family ATP-dependent chromatin remodeling factor SMARCA5 (SNF2H) plays a critical role in regulating meiotic prophase progression during spermatogenesis. Males with germ cell-specific depletion of SMARCA5 are infertile and unable to form sperm. Loss of Smarca5 results in failure of meiotic progression with abnormal spermatocytes beginning at the pachytene stage and an aberrant global increase in chromatin accessibility, especially at genes important for meiotic prophase.

2024-12-05 | GSE279216 | GEO

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