The KMT2 complex protein ASH2L controls meiosis through silencing transposon

ABSTRACT: Meiosis is precisely controlled by complex gene expression programs and involves epigenetic reprogramming and silencing of transposable elements. ASH2L (Absent, small or homeotic 2-like) is a core component of KMT2 complexes conferring H3K4 trimethylation, and plays key roles in mouse embryonic development, neurogenesis, and liver function. However, its role in meiosis remains elusive. Here, we demonstrate an essential role of Ash2l for meiosis. Using a germ cell-specific Ash2l knockout mouse model, we found that Ash2l deficiency leads to meiotic arrest and sterility in both sexes. Ash2l-deficient spermatocytes exhibit failures in chromosomal synapsis, blockades in meiotic recombination, and increased apoptosis. Mechanistically, we found that the Ash2l deficiency results in a global loss of H3K4me3 in promoter regions and significantly decreases expression of thousands of genes, including those for H3K9 di-methylation, DNA methylation and transposon repression, crucial for meiotic prophase I progression. Furthermore, we observed that Ash2l mutant spermatocytes display hypomethylation at transposon sites and ectopic expression of LINE1-ORF1P. Our findings thus reveal a previously unappreciated role of the ASH2L-dependent H3K4me3 modification and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE246296 | GEO | 2024/10/19

REPOSITORIES: GEO