PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos

Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which entails comprehensive erasure of DNA methylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs caused complete male and female sterility, which is preceded by upregulation of LINE1 and IAP transposons and DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation and early embryonic lethality. We detected the PRMT5-catalysed repressive H2A/H4R3me2s modification on LINE1 and IAP in early wildtype PGCs, directly implicating this mark in the maintenance of transposon silencing during DNA hypomethylation. PRMT5 subsequently translocates back to the cytoplasm of PGCs to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA re-methylation. Thus, PRMT5 has a novel direct role in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation PGCs mRNA profiles of embryonic day 11.5 dpc control (Blimp1Cre;Prmt5flox/+) and Prmt5 germ cell knockout (Blimp1Cre;Prmt5 flox/flox) were generated by deep sequencing (SOLiD next generation sequencing).原始生殖细胞（Primordial germ cells，PGCs）与植入前胚胎会经历表观遗传重编程，该过程伴随DNA甲基化的全面清除。我们发现，精氨酸甲基转移酶PRMT5在这一过程中从细胞质易位至细胞核。本研究证实，早期PGCs中PRMT5的条件性敲除会导致雌雄个体完全不育，该表型出现前先伴随LINE1与IAP转座子的上调以及DNA损伤应答激活。类似地，母源-合子型PRMT5的缺失同样会引发IAP上调与早期胚胎致死。我们在野生型早期PGCs中检测到PRMT5催化的LINE1与IAP位点上的抑制性组蛋白修饰H2A/H4R3me2s，直接表明该修饰在DNA低甲基化过程中参与维持转座子沉默。随后，PRMT5会重新易位至PGCs的细胞质，参与此前已报道的PIWI互作RNA（PIWI-interacting RNA，piRNA）通路——该通路通过从头DNA甲基化促进转座子沉默。综上，PRMT5在植入前发育阶段以及全基因组DNA去甲基化时期的PGCs中，在基因组防御方面发挥了全新的直接作用。本研究通过深度测序（SOLiD下一代测序技术）获取了交配后第11.5天胚胎（embryonic day 11.5 dpc）的对照组（Blimp1Cre;Prmt5flox/+）与Prmt5生殖细胞敲除组（Blimp1Cre;Prmt5 flox/flox）的PGCs mRNA转录组数据。