ASH2L is a core component of KMT2 complexes, crucial for H3K4 trimethylation. However, its role in spermatogenesis remains elusive. Here, we demonstrate an essential role of Ash2l for meiotic prophase but dispensable for mitosis in differentiated spermatogonia. Using a germ cell-specific Ash2l knockout mouse model, we reveal that Ash2l deficiency leads to meiotic arrest and sterility in both sexes. Ash2l -deficient spermatocytes exhibit failures in chromosomal synapsis associated with persistent DMC1 foci and γH2AX, resulting in meiocyte loss due to apoptosis. Conversely, Ash2l -deficient differentiated spermatogonia show normal development. Mechanistically, Ash2l deficiency results in a global loss of H3K4me3 in promoter regions and significantly decreases expression of thousands of genes. Among these are genes involved in epigenetic silencing pathways, such as H3K9 di-methylation, DNA methylation and piRNA pathways, that are crucial for transposon repression during meiotic prophase I progression. Supporting this, we observe that Ash2l mutant spermatocytes display ectopic expression of LINE1-ORF1P. Our findings therefore reveal the previously unappreciated role of ASH2L-dependent H3K4me3 modification in spermatogenesis and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.
The ability of neural stem/progenitor cells (NSPCs) to proliferate and differentiate is required through different stages of neurogenesis. Disturbance in the regulation of neurogenesis causes many neurological diseases, such as intellectual disability, autism, and schizophrenia. However, the intrinsic mechanisms of this regulation in neurogenesis remain poorly understood. Here, we report that Ash2l (Absent, small or homeotic discs-like 2), one core component of a multimeric histone methyltransferase complex, is essential for NSPC fate determination during postnatal neurogenesis. Deletion of Ash2l in NSPCs impairs their capacity for proliferation and differentiation, leading to simplified dendritic arbors in adult-born hippocampal neurons and deficits in cognitive abilities. RNA sequencing data reveal that Ash2l primarily regulates cell fate specification and neuron commitment. Furthermore, we identified Onecut2 , a major downstream target of ASH2L characterized by bivalent histone modifications, and demonstrated that constitutive expression of Onecut2 restores defective proliferation and differentiation of NSPCs in adult Ash2l -deficient mice. Importantly, we identified that Onecut2 modulates TGF-β signaling in NSPCs and that treatment with a TGF-β inhibitor rectifies the phenotype of Ash2l -deficient NSPCs. Collectively, our findings reveal the ASH2L-Onecut2-TGF-β signaling axis that mediates postnatal neurogenesis to maintain proper forebrain function.
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