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Nat Commun. 2019 Oct 17;10(1):4705. doi: 10.1038/s41467-019-12455-4.

UHRF1 suppresses retrotransposons and cooperates with PRMT5 and PIWI proteins in male germ cells.

Author information

1
Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
2
Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
3
College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China.
4
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 210029, China.
5
Department of Tissue and Embryology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.
6
Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China.
7
Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. shuiqiaoyuan@hust.edu.cn.
8
Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518057, China. shuiqiaoyuan@hust.edu.cn.

Abstract

DNA methylation, repressive histone marks, and PIWI-interacting RNA (piRNA) are essential for the control of retrotransposon silencing in the mammalian germline. However, it remains unknown how these repressive epigenetic pathways crosstalk to ensure retrotransposon silencing in the male germline. Here, we show that UHRF1 is responsible for retrotransposon silencing and cooperates with repressive epigenetic pathways in male germ cells. Conditional loss of UHRF1 in postnatal germ cells causes DNA hypomethylation, upregulation of retrotransposons, the activation of a DNA damage response, and switches in the global chromatin status, leading to complete male sterility. Furthermore, we show that UHRF1 interacts with PRMT5, an arginine methyltransferase, to regulate the repressive histone arginine modifications (H4R3me2s and H3R2me2s), and cooperates with the PIWI pathway during spermatogenesis. Collectively, UHRF1 regulates retrotransposon silencing in male germ cells and provides a molecular link between DNA methylation, histone modification, and the PIWI pathway in the germline.

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