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

Juan Dong, Xiaoli Wang, Congcong Cao, Yujiao Wen, Akihiko Sakashita, Si Chen, Jin Zhang, Yue Zhang, Liquan Zhou, Mengcheng Luo, Mingxi Liu, Aihua Liao, Satoshi H. Namekawa and Shuiqiao Yuan ()
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Juan Dong: Huazhong University of Science and Technology
Xiaoli Wang: Huazhong University of Science and Technology
Congcong Cao: Huazhong University of Science and Technology
Yujiao Wen: Huazhong University of Science and Technology
Akihiko Sakashita: Cincinnati Children’s Hospital Medical Center
Si Chen: Huazhong University of Science and Technology
Jin Zhang: Huazhong University of Science and Technology
Yue Zhang: Nanjing Medical University
Liquan Zhou: Huazhong University of Science and Technology
Mengcheng Luo: Wuhan University
Mingxi Liu: Nanjing Medical University
Aihua Liao: Huazhong University of Science and Technology
Satoshi H. Namekawa: Cincinnati Children’s Hospital Medical Center
Shuiqiao Yuan: Huazhong University of Science and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12455-4

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