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ISWI chromatin remodeler SMARCA5 is essential for meiotic gene expression and male fertility in mammals

ABSTRACT: Regulation of the transcriptome to promote meiosis is important for sperm development and fertility. However, how chromatin remodeling directs the transcriptome during meiosis in male germ cells is largely unknown. Here, we demonstrate that the ISWI family ATP-dependent chromatin remodeling factor SMARCA5 (SNF2H) plays a critical role in regulating meiotic prophase progression during spermatogenesis. Males with germ cell-specific depletion of SMARCA5 are infertile and unable to form sperm. Loss of Smarca5 results in failure of meiotic progression with abnormal spermatocytes beginning at the pachytene stage and an aberrant global increase in chromatin accessibility, especially at genes important for meiotic prophase.

ORGANISM(S): Mus musculus

PROVIDER: GSE279216 | GEO | 2024/12/05

REPOSITORIES: GEO

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Project description:Dynamic nuclear architecture and chromatin organizations are the key features of the mid- prophase I in mammalian meiosis. Where the chromatin undergoes major changes, including meiosis-specific spatiotemporal arrangements and remodelling, the establishment of chromatin loop–axis structure, pairing, and crossing over between homologous chromosomes, any deficiencies in these events may induce genome instability, subsequently leading to failure to produce gametes and infertility. Despite the significance of chromatin structure, little is known about the location of chromatin marks and the necessity of their balance during meiosis prophase I. Here, we show a thorough cytological study of the surface-spread meiotic chromosomes of mouse spermatocytes for H3K9,14,18,23,27,36, H4K12,16 acetylation, and H3K4,9,27,36 methylation. Active acetylation and methylation marks on H3 and H4, such as H3K9ac, H3K14ac, H3K18ac, H3K36ac, H3K56ac, H4K12ac, H4K16ac, and H3K27me3 and H3K36me3 exhibited pan-nuclear localization away from heterochromatin. In comparison, repressive marks like H3K9me3 are localized to heterochromatin. In addition, we found that the intensities of H3K23ac, H3K27ac, and H3K9me3 enhanced during meiotic prophase I. Further, taking advantage of the delivery of small-molecule chemical inhibitors Methotrexate (MTX; heterochromatin enhancer), HMS-I1 (heterochromatin inhibitor), Anacardic acid (AA; histone acetyltransferase inhibitor), Trichostatin A (TSA; histone deacetylase inhibitor), IOX1 (JmjC demethylases inhibitor), and AZ505 (methyl transferase inhibitor) in seminiferous tubules through the rete testis route, revealed that alteration in histone modifications enhanced the centromere mislocalization, chromosome breakage, altered meiotic recombination and reduced sperm count. Notably, an imbalance in the histone modifications influences the chromosome axis length and chromatin loop size via transcriptional regulation of meiosis- specific genes. Our findings highlight the importance of balanced chromatin modifications in meiotic prophase I chromosome organization and instability.

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ISWI chromatin remodeler SMARCA5 is essential for meiotic gene expression and male fertility in mammals

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