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Argonaute proteins regulate the timing of the spermatogenic transcriptional program

ABSTRACT: Argonaute proteins are best known for their role in microRNA-mediated post-transcriptional gene silencing. Here, we show that AGO3, but not AGO2, localizes to the sex chromatin of pachytene spermatocytes nuclei, where together with AGO4, it is required for full transcriptional silencing of XY-linked genes. Using a triple Ago413-/- mouse, we show that AGO3 and AGO4 are key regulators of spermatogenesis, orchestrating program-wide expression of meiosis-related genes during prophase I, while maintaining silencing of spermiogenesis genes. Premature overexpression of spermiogenesis genes during prophase I in Ago413-/- mice results in subfertility, associated with severe spermiogenesis defects leading to altered sperm morphology and reduced fertilization capability. We also identify BRG1, a BAF complex subunit, as an AGO3 interactor. Loss of AGO3 and AGO4 results in increased BRG1 in spermatocytes, suggesting that AGO3 is needed to help remove BRG1 from the XY chromatin during meiotic sex chromosome inactivation and indicating a role for AGO3 in transcriptional control during meiosis through interaction with the chromatin remodeling machinery.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Qin Fu

LAB HEAD: Qin Fu

PROVIDER: PXD059391 | Pride | 2026-06-22

REPOSITORIES: Pride

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			Action	DRS
	MercedesCarro10460738_AGO4.raw	Raw
	MercedesCarro10460738_IgG.raw	Raw
	MercedesCarro10460738_LFQ.mgf	Mgf
	MercedesCarro10460738_LFQ.msf	Msf
	MercedesCarro10460738_MYC.raw	Raw

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

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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.

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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.

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The ubiquitin-conjugating enzyme HR6B is required for maintenance of X chromosome silencing in mouse spermatocytes and spermatids

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