Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells

Genes and Development - Tập 36 Số 11-12 - Trang 752-763 - 2022
Huijuan Lin1,2, Keren Cheng2, Hiroshi Kubota3, Yemin Lan4, Simone S. Riedel5,6,7, Kazue Kakiuchi3, Kotaro Sasaki2, Kathrin M. Bernt5,6,7, Marisa S. Bartolomei4, Mengcheng Luo1, P. Jeremy Wang2
11School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei Province 430072, China
22Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104, USA
33Laboratory of Cell and Molecular Biology, Department of Animal Science, School of Veterinary Medicine, Kitasato University, Towada, Aomori 034-8628, Japan
44Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
55Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
66Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
77Abramson Cancer Center, Philadelphia, Pennsylvania 19104, USA

Tóm tắt

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 stem cells, 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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Genes and Development

Tập 36 Số 11-12

752-763

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