Epigenetic control of spermatogonial stem cell self-renewal

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Project Summary Males produce sperm continuously through adult life, driven by the renewal of spermatogonial stem cells (SSCs). The long-term objective of this application is to determine the role of a novel epigenetic program that we have recently identified in regulating the renewal of adult SSCs. SSCs can both self-renew and produce progenitor spermatogonia that will differentiate to initiate spermatogenesis. The balance between SSC self- renewal and differentiation is key for life-long production of sperm in adult males. Both SSC transplantation and in vitro SSC cultures have enabled functional studies of SSC and allowed for advancement of translational applications in animal transgenesis. However, while much is known about spermatogenesis, the regulation of SSC self-renewal remains poorly understood. Stem cell renewal requires both stem cell-intrinsic factors and external niche factors, only a handful of which have been identified (PLZF, RB, NANOS2, GDNF, ETV5, etc.). Notably, their functions in SSC self-renewal have been revealed through genetic studies. Despite these advances, the molecular biological control of SSC remains poorly understood. We have identified an epigenetic factor DOT1L, the sole H3K79 methyltransferase, as a novel master regulator of mouse SSC self- renewal. Moreover, by chemically inhibiting DOT1L, we were able to identify specific target genes that likely contribute to SSC renewal. We propose an innovative multi-pronged (genetic, chemical, genomic, and proteomic) approach to comprehensively elucidate this novel epigenetic program in SSCs. As failure in SSC self-renewal leads to a lack of sperm production and thus male infertility, completion of this project will lay a firm foundation for molecular dissection of SSC stem cell renewal and open new avenues of research in SSC biology and reproductive medicine.