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INO80 regulates chromatin accessibility to facilitate suppression of sex-linked gene expression during mouse spermatogenesis

ABSTRACT: The INO80 protein is the main catalytic subunit of the INO80-chromatin remodeling complex, which is critical for DNA repair and transcription regulation in murine spermatocytes. In this study, we explored the role of INO80 in silencing genes on meiotic sex chromosomes in male mice. INO80 immunolocalization at the XY body in pachytene spermatocytes suggested a role for INO80 in the meiotic sex body. Subsequent deletion of Ino80 resulted in high expression of sex-linked genes. Furthermore, the active form of RNA polymerase II at the sex chromosomes of Ino80-null pachytene spermatocytes indicates incomplete inactivation of sex-linked genes. A reduction in the recruitment of initiators of meiotic sex chromosome inhibition (MSCI) argues for INO80-facilitated recruitment of DNA repair factors required for silencing sex-linked genes. This role of INO80 is independent of a common INO80 target, H2A.Z. Instead, in the absence of INO80, a reduction in chromatin accessibility at DNA repair sites occurs on the sex chromosomes. These data suggest a role for INO80 in DNA repair factor localization, thereby facilitating the silencing of sex-linked genes during the onset of pachynema.

ORGANISM(S): Mus musculus

PROVIDER: GSE221682 | GEO | 2024/10/07

REPOSITORIES: GEO

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INO80 regulates chromatin accessibility to facilitate suppression of sex-linked gene expression during mouse spermatogenesis

Project description:The INO80 protein is the main catalytic subunit of the INO80-chromatin remodeling complex, which is critical for DNA repair and transcription regulation in murine spermatocytes. In this study, we explored the role of INO80 in silencing genes on meiotic sex chromosomes in male mice. INO80 immunolocalization at the XY body in pachytene spermatocytes suggested a role for INO80 in the meiotic sex body. Subsequent deletion of Ino80 resulted in high expression of sex-linked genes. Furthermore, the active form of RNA polymerase II at the sex body of Ino80-null pachytene spermatocytes indicates incomplete inactivation of sex-linked genes. A reduction in the recruitment of initiators of meiotic sex chromosome inhibition (MSCI) argues for INO80-facilitated recruitment of DNA repair factors required for silencing sex-linked genes. This role of INO80 is independent of a common INO80 target H2A.Z. Instead, in the absence of INO80, a reduction in chromatin accessibility at DNA repair sites occurs on the sex chromosomes. These data suggest a role for INO80 in DNA repair factor localization, thereby facilitating the silencing of sex-linked genes during the onset of pachynema.

2024-10-07 | GSE273472 | GEO

INO80 requires a polycomb subunit to regulate the establishment of poised chromatin in murine spermatocytes [RNA-seq]

Project description:INO80 is the catalytic subunit of the multi-subunit INO80-chromatin remodeling complex that has been implicated in DNA replication, repair, and transcription regulation. Ino80-deficiency in murine spermatocytes (Ino80cKO) results in pachytene arrest of spermatocytes, due to incomplete synapsis and aberrant DNA double-strand break repair (DSBR) that leads to apoptosis. We explored the mechanism by which INO80 mediates meiotic progression. RNA-seq on Ino80cKO spermatocytes revealed major changes in transcription, indicating that an aberrant transcription program arises upon INO80 depletion. In Ino80WTspermatocytes, genome-wide analysis showed that INO80-binding sites were mostly promoter proximal and necessary for the regulation of spermatogenic gene expression, primarily of premeiotic and meiotic genes. Further, most of the genes poised for activity, as well as those genes that are active, shared INO80 binding. In Ino80cKO spermatocytes, most poised genes demonstrated de-repression due to reduced H3K27me3 enrichment, and in turn showed increased expression levels. INO80 interacts with the core PRC2 complex member SUZ12 and promotes its recruitment. Further, INO80 mediates H2A.Z incorporation at the poised promoters, which was reduced in Ino80cKO spermatocytes. Taken together, INO80 is emerging as a major regulator of the meiotic transcription program by mediating poised chromatin establishment through SUZ12 binding.

2021-12-21 | GSE179583 | GEO

INO80 requires a polycomb subunit to regulate the establishment of poised chromatin in murine spermatocytes [CUT&RUN]

2021-12-21 | GSE179580 | GEO

INO80 requires a polycomb subunit to regulate the establishment of poised chromatin in murine spermatocytes [ChIP-seq]

2021-12-21 | GSE179579 | GEO

INO80 requires a polycomb subunit to regulate the establishment of poised chromatin in murine spermatocytes [ATAC-seq]

2021-12-21 | GSE179577 | 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

Zfy genes are required for efficient meiotic sex chromosome inactivation (MSCI) in spermatocytes

Project description:During spermatogenesis, germ cells that fail to synapse their chromosomes or fail to undergo meiotic sex chromosome inactivation (MSCI) are eliminated via apoptosis during mid-pachytene. Previous work showed that Y-linked genes Zfy1 and Zfy2 act as “executioners” for this checkpoint, and that wrongful expression of either gene during pachytene triggers germ cell death. Here, we show that in mice, Zfy genes are also necessary for efficient MSCI and the sex chromosomes are not correctly silenced in Zfy-deficient spermatocytes. In addition to this microarray data set, qPCR and RNA FISH data were used to confirm that MSCI is leaky in males lacking Zfy genes. The array data demonstrates that transgenic restoration of Zfy2 corrects the MSCI leakage phenotype. The associated RNA FISH data demonstrates that Zfy1 and Zfy2 are both able to correct the leakage phenotype.

2016-10-05 | GSE87598 | GEO

ATF7IP2/MCAF2 directs H3K9 methylation and meiotic gene regulation in the male germline [CUT&RUN, CUT&Tag]

Project description:H3K9 tri-methylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that, in male meiosis, ATF7IP2 amasses on autosomal and X pericentric heterochromatin, spreads through the entirety of the sex chromosomes, and accumulates on thousands of autosomal promoters and retrotransposon loci. On the sex chromosomes, which undergo meiotic sex chromosome inactivation (MSCI), the DNA damage response pathway recruits ATF7IP2 to X pericentric heterochromatin, where it facilitates the recruitment of SETDB1, a histone methyltransferase that catalyzes H3K9me3. In the absence of ATF7IP2, male germ cells are arrested in meiotic prophase. Analyses of ATF7IP2-deficient meiosis reveal the protein’s essential roles in the maintenance of MSCI, suppression of retrotransposons, and global activation of autosomal genes. We propose that ATF7IP2 is a downstream effector of the DDR pathway in meiosis that coordinates the organization of heterochromatin and gene regulation through the spatial regulation of SETDB1-mediated H3K9me3 deposition. CUT&RUN of H3K9me3 in Atf7ip2+/+ and Atf7ip2-/- pachytene spermatocytes and CUT&Tag of ATF7IP2 in C57/B6 WT pachytene spermatocytes.

2024-02-14 | GSE244083 | GEO

The male pachynema-specific protein MAPS drives phase separation in vitro and regulates sex body formation in vivo

Project description:Highly dynamic chromosome remodeling and extensive nuclear compartmentalization occur during mammalian meiotic prophase I. We report here that mouse spermatocytes lacking MAPS, the male pachynema-specific protein, exhibit multiple pachytene defects, including disordered chromatin accessibility, interrupted nucleosome composition, and globally altered transcription, accompanied by disturbed nucleus phase formation. Adult Maps−/− pachytene spermatocytes lack sex body formation and exhibit improper autosomal chromatin condensation, which can be attributed to the feature of MAPS to mediate phase separation through its unique intrinsically disordered regions (IDRs), amino acids 2-9. MAPS protein with deletion of IDR failed to form a distinguishable phase in vitro and in cultured cells, and remarkably, MAPS IDR-deleted male mice suffer from pachytene arrest and sterility, with a typical absence of sex body and less condensed autosomal chromosomes, similar to Maps−/− mice. Thus, the nucleus phase separation mediated by MAPS may be essential for male pachynema progression in mice.

2024-06-25 | GSE234448 | GEO

Meiotic Consequences of Genetic Extension of Unsynapsed Autosomal Chromatin

Project description:We investigated the influence of extension of autosomal asynapsis on expression profiles during spermatogenesis. We used the mouse autosomal translocation T(16;17)43H (abbreviated T43H) and t12 haplotype, a natural variant of Chr 17 encompassing four adjacent non-overlapping inversions proximal to the T43H translocation breakpoint, as a model. The presence of t12 haplotype in trans to the T43H translocation resulted in stringent spermatogenic block and in more complete silencing of genes surrounding the T43H translocation break. Strikingly, silencing of the unsynapsed autosomal chromatin preceded the inactivation of the sex chromosomes (MSCI) and was apparent already in the population of pre-mid pachytene spermatocytes and testes of 15 days old males. Populations of pre-mid-pachytene spermatocytes were isolated from Ttf+/+T43H and t12+/+T43 males in three biological replicates. Their expression was compared to two biological replicates of the populations of pre-mid pachytene spermatocytes and mid-late pachytene spermatocytes obtained from C57BL/10J fertile males. Independently, testicular RNA was isolated from 15 days old Ttf+/+T43H and t12+/+T43 males in three biological replicates and the expression was compared to the testicular expression of two 15 days old C57BL/6J males.

2014-05-09 | E-GEOD-29177 | biostudies-arrayexpress

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