Pluto Bioinformatics

GSE134521: Gcn5-mediated histone acetylation governs nucleosome dynamics in spermiogenesis [RNA-Seq]

Bulk RNA sequencing

During mammalian spermatogenesis, male germ cells undergo dramatic reorganization of chromatin, whereby 90-99% of histones are evicted and replaced by protamines. This reorganization prominently features histone acetylation to loosen chromatin structure. Given the potential role of retained histones in fertility and early embryonic development, the genomic location of retained nucleosomes is of great interest. However, the ultimate position and mechanisms underlying nucleosome eviction/retention are poorly understood, including several studies utilizing MNase-seq methodologies, but reporting remarkably dissimilar locations. Here, we utilized ATAC-seq to determine the location of retained nucleosomes in mouse sperm and found enrichment at promoters, but also retention at inter- and intragenic regions, and repetitive elements. We further investigated nucleosome eviction/retention by generating pre-meiotic, germ cell specific, conditional knockout mice for the histone acetyltransferase Gcn5, a key histone acetyltransferase. Gcn5cKO germ cells exhibited abnormal chromatin dynamics during spermiogenesis, including diminished nucleosome eviction leading to increased histone retention in sperm. These mice exhibited severe reproductive phenotypes: abnormal sperm production, sperm morphology, and ultimately, male infertility. Our findings demonstrate Gcn5 mediated histone acetylation promotes chromatin accessibility and nucleosome eviction in spermiogenesis, and that loss of histone acetylation leads to defects that disrupt male fertility and potentially, early embryogenesis. SOURCE: Gregory DonahueZaret Lab The University of Pennsylvania