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

• Published in: eLife Vol. 12
• Main Authors: Menon, Debashish U, Chakraborty, Prabuddha, Murcia, Noel, Magnuson, Terry
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 26.11.2024; eLife Sciences Publications, Ltd
• Subjects: Animals; ARID1A; BRG1 protein; Cell death; Cell division; Chromatids; Chromatin; chromatin remodelers; Developmental Biology; DNA damage; DNA repair; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-directed RNA polymerase; Gene regulation; Gene Silencing; Genetics and Genomics; Germ cells; Histones; Histones - genetics; Histones - metabolism; Immunofluorescence; Localization; Male; Males; Meiosis; Meiosis - genetics; meiotic sex chromosome; Mice; Mouse; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proteins; Recombinase; RNA polymerase; Sex chromosomes; Sex Chromosomes - genetics; Sex linkage; Somatic chromosomes; Spermatogenesis; Testes; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; genetics; Mouse; meiotic sex chromosome; gene regulation; sex-linked DNA repair; developmental biology; spermatogenesis; genomics; ARID1A; chromatin remodelers
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88024

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 1 a), appeared enriched on the male sex chromosomes during diplonema of meiosis I. Germ cells showing a Cre-induced loss of ARID1A arrested in pachynema and failed to repress sex-linked genes, indicating a defective MSCI. Mutant sex chromosomes displayed an abnormal presence of elongating RNA polymerase II coupled with an overall increase in chromatin accessibility detectable by ATAC-seq. 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.