UHRF1 interacts with snRNAs and regulates alternative splicing in mouse spermatogonial stem cells.

Life-long male fertility relies on exquisite homeostasis and the development of spermatogonial stem cells (SSCs); however, the underlying molecular genetic and epigenetic regulation in this equilibrium process remains unclear. Here, we document that UHRF1 interacts with snRNAs to regulate pre-mRNA alternative splicing in SSCs and is required for the homeostasis of SSCs in mice. Genetic deficiency of UHRF1 in mouse prospermatogonia results in gradual loss of spermatogonial stem cells, eventually leading to Sertoli-cell-only syndrome (SCOS) and male infertility. Comparative RNA-seq data provide evidence that Uhrf1 ablation dysregulates previously reported SSC maintenance- and differentiation-related genes. We further found that UHRF1 could act as an alternative RNA splicing regulator and interact with Tle3 transcripts to regulate its splicing event in spermatogonia. Collectively, our data reveal a multifunctional role for UHRF1 in regulating gene expression programs and alternative splicing during SSC homeostasis, which may provide clues for treating human male infertility.