RIKEN BioResource Center, Ibaraki 305-0074, Japan.
Cellular Memory Laboratory, RIKEN Wako, Saitama 351-0198, Japan; Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Cell Rep. 2017 Sep 19;20(12):2756-2765. doi: 10.1016/j.celrep.2017.08.088.
At fertilization, the paternal genome undergoes extensive reprogramming through protamine-histone exchange and active DNA demethylation, but only a few maternal factors have been defined in these processes. We identified maternal Mettl23 as a protein arginine methyltransferase (PRMT), which most likely catalyzes the asymmetric dimethylation of histone H3R17 (H3R17me2a), as indicated by in vitro assays and treatment with TBBD, an H3R17 PRMT inhibitor. Maternal histone H3.3, which is essential for paternal nucleosomal assembly, is unable to be incorporated into the male pronucleus when it lacks R17me2a. Mettl23 interacts with Tet3, a 5mC-oxidizing enzyme responsible for active DNA demethylation, by binding to another maternal factor, GSE (gonad-specific expression). Depletion of Mettl23 from oocytes resulted in impaired accumulation of GSE, Tet3, and 5hmC in the male pronucleus, suggesting that Mettl23 may recruit GSE-Tet3 to chromatin. Our findings establish H3R17me2a and its catalyzing enzyme Mettl23 as key regulators of paternal genome reprogramming.
在受精过程中，父系基因组通过鱼精蛋白-组蛋白交换和活性 DNA 去甲基化经历广泛的重编程，但在这些过程中只定义了少数母体因素。我们鉴定了母体 Mettl23 作为一种蛋白精氨酸甲基转移酶（PRMT），它很可能催化组蛋白 H3R17（H3R17me2a）的不对称二甲基化，这一点通过体外测定和 H3R17 PRMT 抑制剂 TBBD 的处理得到了证实。母体组蛋白 H3.3 对于父本核小体组装是必不可少的，但当其缺乏 R17me2a 时，无法被纳入雄性原核。Mettl23 通过与 Tet3（一种负责活性 DNA 去甲基化的 5mC 氧化酶）相互作用，由另一个母体因子 GSE（性腺特异性表达）结合来实现。从卵母细胞中耗尽 Mettl23 会导致 GSE、Tet3 和 5hmC 在雄性原核中的积累受损，这表明 Mettl23 可能将 GSE-Tet3 招募到染色质上。我们的发现确立了 H3R17me2a 及其催化酶 Mettl23 作为父系基因组重编程的关键调节剂。
