Kim Shinseog, Günesdogan Ufuk, Zylicz Jan J, Hackett Jamie A, Cougot Delphine, Bao Siqin, Lee Caroline, Dietmann Sabine, Allen George E, Sengupta Roopsha, Surani M Azim
Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development, and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK; Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; College of Life Science, Inner Mongolia University, No. 235 Da Xue Xi Road, Huhhot, Inner Mongolia 010021, China.
Mol Cell. 2014 Nov 20;56(4):564-79. doi: 10.1016/j.molcel.2014.10.003. Epub 2014 Nov 6.
Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which includes comprehensive DNA demethylation. 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 causes complete male and female sterility, preceded by the upregulation of LINE1 and IAP transposons as well as activation of a DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation. PRMT5 is necessary for the repressive H2A/H4R3me2s chromatin modification on LINE1 and IAP transposons in PGCs, directly implicating this modification in transposon silencing during DNA hypomethylation. PRMT5 translocates back to the cytoplasm subsequently, to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA remethylation. Thus, PRMT5 is directly involved in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation.
原始生殖细胞（PGCs）和植入前胚胎会经历表观遗传重编程，其中包括全面的DNA去甲基化。我们发现，精氨酸甲基转移酶PRMT5在此过程中从细胞质转移至细胞核。在此我们表明，早期PGCs中PRMT5的条件性缺失会导致完全的雄性和雌性不育，在此之前LINE1和IAP转座子会上调以及DNA损伤反应被激活。同样，母源合子PRMT5的缺失也会导致IAP上调。PRMT5对于PGCs中LINE1和IAP转座子上抑制性的H2A/H4R3me2s染色质修饰是必需的，这直接表明这种修饰在DNA低甲基化过程中对转座子沉默有作用。随后PRMT5会重新回到细胞质，参与之前描述的通过从头DNA甲基化促进转座子沉默的PIWI相互作用RNA（piRNA）途径。因此，PRMT5在植入前发育期间以及全球DNA去甲基化时的PGCs中直接参与基因组防御。
