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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE332917 | GEO | 2026/06/22

REPOSITORIES: GEO

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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.

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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.

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