ARID1A governs the silencing of sex-linked transcription during male meiosis in the mouse

We present evidence implicating the BAF (BRG1/BRM Associated Factor) chromatin remodeler in meiotic sex chromosome inactivation (MSCI). By immunofluorescence (IF), the putative BAF DNA binding subunit, ARID1A (AT-rich Interaction Domain 1a), appeared enriched on the male sex chromosomes during diplo...

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Bibliographic Details
Published inbioRxiv
Main Authors Menon, Debashish U, Chakraborty, Prabuddha, Murcia, Noel, Magnuson, Terry
Format Journal Article Paper
LanguageEnglish
Published United States Cold Spring Harbor Laboratory Press 28.06.2024
Cold Spring Harbor Laboratory
Edition1.4
Subjects
BRG1 protein
Chromatids
Chromatin
Developmental Biology
DNA repair
DNA-directed RNA polymerase
Gene regulation
Gene silencing
Germ cells
Histones
Immunofluorescence
Localization
Meiosis
Recombinase
RNA polymerase
Sex chromosomes
Sex linkage
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Summary:We present evidence implicating the BAF (BRG1/BRM Associated Factor) chromatin remodeler in meiotic sex chromosome inactivation (MSCI). By immunofluorescence (IF), the putative BAF DNA binding subunit, ARID1A (AT-rich Interaction Domain 1a), appeared enriched on the male sex chromosomes during diplonema of meiosis I. Those germ cells showing a Cre-induced loss of ARID1A were arrested in pachynema and failed to repress sex-linked genes, indicating a defective MSCI. Consistent with this defect, mutant sex chromosomes displayed an abnormal presence of elongating RNA polymerase II coupled with an overall increase in chromatin accessibility detectable by ATAC-seq. By investigating potential mechanisms underlying these anomalies, we identified a role for ARID1A in promoting the preferential enrichment of the histone variant, H3.3, on the sex chromosomes, a known hallmark of MSCI. Without ARID1A, the sex chromosomes appeared depleted of H3.3 at levels resembling autosomes. Higher resolution analyses by CUT&RUN revealed shifts in sex-linked H3.3 associations from discrete intergenic sites and broader gene-body domains to promoters in response to the loss of ARID1A. Several sex-linked sites displayed ectopic H3.3 occupancy that did not co-localize with DMC1 (DNA Meiotic Recombinase 1). This observation suggests a requirement for ARID1A in DMC1 localization to the asynapsed sex chromatids. We conclude that ARID1A-directed H3.3 localization influences meiotic sex chromosome gene regulation and DNA repair.
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Competing Interest Statement: The authors have declared no competing interest.
ISSN:2692-8205
2692-8205
DOI:10.1101/2023.05.25.542290