Zhao Quan, Rank Gerhard, Tan Yuen T, Li Haitao, Moritz Robert L, Simpson Richard J, Cerruti Loretta, Curtis David J, Patel Dinshaw J, Allis C David, Cunningham John M, Jane Stephen M
Rotary Bone Marrow Research Laboratories, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, VIC 3050, Australia.
Molecular Immunology and Cancer Research Center, The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Nat Struct Mol Biol. 2009 Mar;16(3):304-311. doi: 10.1038/nsmb.1568. Epub 2009 Feb 22.
Mammalian gene silencing is established through methylation of histones and DNA, although the order in which these modifications occur remains contentious. Using the human beta-globin locus as a model, we demonstrate that symmetric methylation of histone H4 arginine 3 (H4R3me2s) by the protein arginine methyltransferase PRMT5 is required for subsequent DNA methylation. H4R3me2s serves as a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif. Loss of the H4R3me2s mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. In primary erythroid progenitors from adult bone marrow, H4R3me2s marks the inactive methylated globin genes coincident with localization of PRMT5. Our findings define DNMT3A as both a reader and a writer of repressive epigenetic marks, thereby directly linking histone and DNA methylation in gene silencing.
哺乳动物基因沉默是通过组蛋白和DNA的甲基化建立的，尽管这些修饰发生的顺序仍存在争议。我们以人类β-珠蛋白基因座为模型，证明蛋白质精氨酸甲基转移酶PRMT5对组蛋白H4精氨酸3（H4R3me2s）的对称甲基化是随后DNA甲基化所必需的。H4R3me2s作为DNA甲基转移酶DNMT3A的直接结合靶点，DNMT3A通过含有PHD基序的ADD结构域相互作用。通过短发夹RNA介导的PRMT5敲低导致H4R3me2s标记缺失，进而导致DNMT3A结合减少、DNA甲基化丧失和基因激活。在来自成年骨髓的原代红细胞祖细胞中，H4R3me2s标记着与PRMT5定位一致的无活性甲基化珠蛋白基因。我们的研究结果将DNMT3A定义为抑制性表观遗传标记的读取器和写入器，从而在基因沉默中直接将组蛋白和DNA甲基化联系起来。
