G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis
G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis
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DOI：
10.1101/gad.989402
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发表时间：
2002-07-15
影响因子：
10.5
通讯作者：
Shinkai, Y
中科院分区：
文献类型：
--
作者：
Tachibana, M;Sugimoto, K;Shinkai, Y
组蛋白尾部的共价修饰对于转录调控、有丝分裂染色体浓缩和异染色质形成至关重要。由Suv 39 h家族蛋白催化的组蛋白H3赖氨酸9（H3-K9）甲基化对于建立臂间异染色质的结构是必不可少的。我们最近发现了一种哺乳动物组蛋白甲基转移酶（HMTase），G9 a，它在体外对H3-K9具有很强的HMTase活性。为了研究G9 a的体内功能，我们产生了G9 a缺陷小鼠和胚胎干细胞（ES）。我们发现，H3-K9甲基化在G9 a缺陷胚胎中急剧下降，表现出严重的生长迟缓和早期致死性。与野生型细胞相比，G9 a缺陷型ES细胞也表现出降低的H3-K9甲基化，表明G9 a是体内显性H3-K9 HMT酶。重要的是，G9 a的缺失主要在常染色质区消除了甲基化H3-K9。最后，G9 a发挥转录抑制功能，这取决于其HMTase活性。我们的研究结果表明，常染色体H3-K9甲基化调控的G9 a是必不可少的早期胚胎发生，并参与转录抑制的发育基因。
Covalent modification of histone tails is crucial for transcriptional regulation, mitotic chromosomal condensation, and heterochromatin formation. Histone H3 lysine 9 (H3-K9) methylation catalyzed by the Suv39h family proteins is essential for establishing the architecture of pericentric heterochromatin. We recently identified a mammalian histone methyltransferase (HMTase), G9a, which has strong HMTase activity towards H3-K9 in vitro. To investigate the in vivo functions of G9a, we generated G9a-deficient mice and embryonic stem (ES) cells. We found that H3-K9 methylation was drastically decreased in G9a-deficient embryos, which displayed severe growth retardation and early lethality. G9a-deficient ES cells also exhibited reduced H3-K9 methylation compared to wild-type cells, indicating that G9a is a dominant H3-K9 HMTase in vivo. Importantly, the loss of G9a abolished methylated H3-K9 mostly in euchromatic regions. Finally, G9a exerted a transcriptionally suppressive function that depended on its HMTase activity. Our results indicate that euchromatic H3-K9 methylation regulated by G9a is essential for early embryogenesis and is involved in the transcriptional repression of developmental genes.