Role of distinct surfaces of the G9a ankyrin repeat domain in histone and DNA methylation during embryonic stem cell self-renewal and differentiation.
Role of distinct surfaces of the G9a ankyrin repeat domain in histone and DNA methylation during embryonic stem cell self-renewal and differentiation.
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DOI：
10.1186/1756-8935-7-27
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发表时间：
2014
影响因子：
3.9
通讯作者：
Stallcup MR
中科院分区：
文献类型：
--
作者：
Bittencourt D;Lee BH;Gao L;Gerke DS;Stallcup MR
表观遗传修饰，如组蛋白和DNA甲基化是在胚胎干细胞（ESC）分化过程中沉默多能性基因所必需的。G9 a是常染色质中主要的组蛋白H3 Lys 9（H3 K9）甲基转移酶，并且是ESC分化期间多能性Oct 3/4的关键调节因子的从头DNA甲基化所需的。令人惊讶的是，G9 a的催化活性不是其在从头DNA甲基化中的作用所必需的，并且G9 a在该过程中的精确分子机制知之甚少。已经表明，G9 a锚蛋白重复结构域可以与H3 K9 me 2和DNA甲基转移酶DNMT 3A相互作用，可以通过桥接DNMT 3A和H3 K9 me 2标记的染色质之间的相互作用来促进从头DNA甲基化。在这里，我们证明了G9 a锚蛋白结构域H3 K9 me 2结合功能是不需要的从头DNA甲基化的Oct 3/4在ESC分化。此外，我们表明G9 a锚蛋白结构域和DNMT 3A之间的相互作用不足以确保有效的从头DNA甲基化。更重要的是，我们表征了G9 a锚蛋白结构域（Asp 905）的特定残基，该残基对于维持未分化ESC中的细胞H3 K9 me 2水平和在分化期间建立从头DNA甲基化都至关重要。这些结果代表了一个令人兴奋的突破，它揭示了1）G9 a锚蛋白结构域在全局组蛋白H3 K9甲基化中的意想不到的关键生物学功能，以及2）对G9 a在ESC分化期间调节Oct 3/4的从头DNA甲基化的分子机制和相互作用表面的有价值的见解。
Epigenetic modifications such as histone and DNA methylation are essential for silencing pluripotency genes during embryonic stem cell (ESC) differentiation. G9a is the major histone H3 Lys9 (H3K9) methyltransferase in euchromatin and is required for the de novo DNA methylation of the key regulator of pluripotency Oct3/4 during ESC differentiation. Surprisingly, the catalytic activity of G9a is not required for its role in de novo DNA methylation and the precise molecular mechanisms of G9a in this process are poorly understood. It has been suggested that the G9a ankyrin repeat domain, which can interact with both H3K9me2 and the DNA methyltransferase DNMT3A, could facilitate de novo DNA methylation by bridging the interaction between DNMT3A and H3K9me2-marked chromatin. Here, we demonstrate that the G9a ankyrin domain H3K9me2-binding function is not required for the de novo DNA methylation of Oct3/4 during ESC differentiation. Moreover, we show that the interaction between the G9a ankyrin domain and DNMT3A is not sufficient to ensure efficient de novo DNA methylation. More importantly, we characterize a specific residue of the G9a ankyrin domain (Asp905) that is critical for both maintaining cellular H3K9me2 levels in undifferentiated ESCs and for the establishment of de novo DNA methylation during differentiation. These results represent an exciting breakthrough, which reveals 1) an unexpected critical biological function of the G9a ankyrin domain in global histone H3K9 methylation and 2) valuable insights into the molecular mechanisms and interaction surfaces through which G9a regulates de novo DNA methylation of Oct3/4 during ESC differentiation.
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影响因子：
30.8
作者：
Wen, Bo;Wu, Hao;Shinkai, Yoichi;Irizarry, Rafael A.;Feinberg, Andrew P.
通讯作者：
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影响因子：
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通讯作者：
Ren B
影响因子：
10.5
作者：
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通讯作者：
Shinkai, Y
影响因子：
16.8
作者：
Collins, Robert E.;Northrop, Jeffrey P.;Cheng, Xiaodong
通讯作者：
Cheng, Xiaodong
影响因子：
10.5
作者：
Tachibana, M;Sugimoto, K;Shinkai, Y
通讯作者：
Shinkai, Y