Huijuan Lin1,
2,
8,
Keren Cheng2,
8,
Hiroshi Kubota3,
Yemin Lan4,
Simone S. Riedel5,
6,
7,
Kazue Kakiuchi3,
Kotaro Sasaki2,
Kathrin M. Bernt5,
6,
7,
Marisa S. Bartolomei4,
Mengcheng Luo1 and
P. Jeremy Wang2
1School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei Province 430072, China;
2Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104,
USA;
3Laboratory of Cell and Molecular Biology, Department of Animal Science, School of Veterinary Medicine, Kitasato University,
Towada, Aomori 034-8628, Japan;
4Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, USA;
5Division of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;
6Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
7Abramson Cancer Center, Philadelphia, Pennsylvania 19104, USA
Corresponding authors: pwangvet.upenn.edu, luomengchengwhu.edu.cn
↵8 These authors contributed equally to this work.
Abstract
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.
Received March 9, 2022.
Accepted June 6, 2022.
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