Journal
GENES & DEVELOPMENT
Volume 36, Issue 11-12, Pages 752-763Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.349550.122
Keywords
DOT1L; epigenetics; adult stem cell; self-renewal; spermatogonial stem cell; transplantation; histone methyltransferase
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Funding
- National Institute of Child Health and Human Development [P50HD068157]
- National Natural Science Foundation of China [31771588]
- China Scholarship Council fellowship
- Japan Society for the Promotion of Science KAKENHI [JP21K19194]
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This study identifies the critical role of DOT1L in the self-renewal of spermatogonial stem cells, mediated by promoting the expression of fate-determining transcription factors HoxC and accumulation of H3K79me2 at specific genes.
Self-renewal of spermatogonial stem cells is vital to lifelong production of male gametes and thus fertility. However, the underlying mechanisms remain enigmatic. Here, we show that DOT1L, the sole H3K79 methyltransferase, is required for spermatogonial stem cell self-renewal. Mice lacking DOT1L fail to maintain spermatogonial stemcells, characterized by a sequential loss of germ cells from spermatogonia to spermatids and ultimately a Sertoli cell only syndrome. Inhibition of DOT1L reduces the stem cell activity after transplantation. DOT1L promotes expression of the fate-determining HoxC transcription factors in spermatogonial stem cells. Furthermore, H3K79me2 accumulates at HoxC9 and HoxC10 genes. Our findings identify an essential function for DOT1L in adult stem cells and provide an epigenetic paradigm for regulation of spermatogonial stem cells.
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