DNA甲基化
生物
DNMT3B型
甲基化
DNA甲基转移酶
胚胎干细胞
表观遗传学
细胞生物学
分子生物学
遗传学
DNA去甲基化
甲基转移酶
RNA导向的DNA甲基化
CpG站点
同源盒蛋白纳米
DNA
染色质
干细胞
5-甲基胞嘧啶
亚硫酸氢盐测序
重编程
表观遗传学
基因
基因表达
作者
Nicolas Veland,Yue Lu,Swanand Hardikar,Sally Gaddis,Yang Zeng,Bigang Liu,Marcos R. Estecio,Yoko Takata,Kevin K. Lin,Mary W. Tomida,Jianjun Shen,Debapriya Saha,Humaira Gowher,Hongbo Zhao,Taiping Chen
摘要
DNMT3L (DNMT3-like), a member of the DNMT3 family, has no DNA methyltransferase activity but regulates de novo DNA methylation. While biochemical studies show that DNMT3L is capable of interacting with both DNMT3A and DNMT3B and stimulating their enzymatic activities, genetic evidence suggests that DNMT3L is essential for DNMT3A-mediated de novo methylation in germ cells but is dispensable for de novo methylation during embryogenesis, which is mainly mediated by DNMT3B. How DNMT3L regulates DNA methylation and what determines its functional specificity are not well understood. Here we show that DNMT3L-deficient mouse embryonic stem cells (mESCs) exhibit downregulation of DNMT3A, especially DNMT3A2, the predominant DNMT3A isoform in mESCs. DNA methylation analysis of DNMT3L-deficient mESCs reveals hypomethylation at many DNMT3A target regions. These results confirm that DNMT3L is a positive regulator of DNA methylation, contrary to a previous report that, in mESCs, DNMT3L regulates DNA methylation positively or negatively, depending on genomic regions. Mechanistically, DNMT3L forms a complex with DNMT3A2 and prevents DNMT3A2 from being degraded. Restoring the DNMT3A protein level in DNMT3L-deficient mESCs partially recovers DNA methylation. Thus, our work uncovers a role for DNMT3L in maintaining DNMT3A stability, which contributes to the effect of DNMT3L on DNMT3A-dependent DNA methylation.
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