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

Juan Dong,Liquan Zhou,Congcong Cao,Si Chen,Mingxi Liu,Mengcheng Luo,Xiaoli Wang,Satoshi H Namekawa,Akihiko Sakashita,Shuiqiao Yuan,Jin Zhang,Yue Zhang,Yujiao Wen,Aihua Liao

doi:10.1038/s41467-019-12455-4

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.

Highlights

DNA methylation, repressive histone marks, and PIWI-interacting RNA are essential for the control of retrotransposon silencing in the mammalian germline
UHRF1 was abundant in the nuclei of neonatal prospermatonia at postnatal day 0 (P0), spermatogonia, late pachytene spermatocytes and early round spermatids; by comparison, UHRF1 was strongly expressed in the cytoplasm of fetal prospermatogonia at E15.5, pre-leptotene, leptotene, zygotene and early pachytene spermatocytes (Fig. 1a, b, Supplementary Fig. 2b)
The current study demonstrates that UHRF1 is indispensable for spermatogenesis and participates in silencing retrotransposons during postnatal germ cell development

Summary

Introduction

DNA methylation, repressive histone marks, and PIWI-interacting RNA (piRNA) are essential for the control of retrotransposon silencing in the mammalian germline. It remains unknown how these repressive epigenetic pathways crosstalk to ensure retrotransposon silencing in the male germline. 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. We discovered that UHRF1 is required for suppression of retrotransposons and identified a critical role for UHRF1 in cooperation with UHRF1, PRMT5, and PIWI proteins in male meiosis These results unveil UHRF1 as a molecular link among DNA methylation, repressive histone marks and the PIWI pathway to safeguard germ cell genomic integrity during spermatogenesis

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Conclusion