The H3K4 methyltransferase Setd1a is first required at the epiblast stage, whereas Setd1b becomes essential after gastrulation
The H3K4 methyltransferase Setd1a is first required at the epiblast stage, whereas Setd1b becomes essential after gastrulation
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DOI：
10.1242/dev.098152
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发表时间：
2014-03-01
期刊：
影响因子：
4.6
通讯作者：
Anastassiadis, Konstantinos
中科院分区：
文献类型：
--
作者：
Bledau, Anita S.;Schmidt, Kerstin;Anastassiadis, Konstantinos
组蛋白3赖氨酸4 （H3K4）甲基化是一个普遍的表观遗传标记。在哺乳动物中，有6个H3K4甲基转移酶与酵母Set1和蝇三胸相关，包括Set1的两个同源基因：Setd1a和Setd1b。本研究表明，小鼠原肠胚形成需要Setd1a基因，而缺乏Setd1a基因的胚胎可以存活到E11.5，但发育严重迟缓。敲除Setd1a的胚胎植入，但不经过外胚层。此外，Setd1a在内部细胞团形成之前是不需要的，在这个阶段它已经取代了Mll2作为主要的H3K4甲基转移酶。Setd1a是胚胎、外胚层和神经干细胞存活和神经干细胞重编程所必需的，而Setd1b则是可有可无的。胚胎干细胞中Setd1a的缺失导致大量H3K4甲基化、多能性基因表达和增殖的快速丧失，并伴有G1堆积。Setd1b过表达不能挽救胚胎干细胞因Setd1a缺失而导致的增殖缺陷。Setd1a的精确发育要求表明原肠胚形成是由主要H3K4甲基转移酶之间的开关调节的。
Histone 3 lysine 4 (H3K4) methylation is a universal epigenetic mark. In mammals, there are six H3K4 methyltransferases related to yeast Set1 and fly Trithorax, including two orthologs of Set1: Setd1a and Setd1b. Here we show that mouse Setd1a is required for gastrulation, whereas Setd1b-deficient embryos survive to E11.5 but are grossly retarded. Setd1a knockout embryos implant but do not proceed past the epiblast. Furthermore, Setd1a is not required until the inner cell mass has formed, at which stage it has replaced Mll2 as the major H3K4 methyltransferase. Setd1a is required for embryonic, epiblast and neural stem cell survival and neural stem cell reprogramming, whereas Setd1b is dispensable. Deletion of Setd1a in embryonic stem cells resulted in rapid losses of bulk H3K4 methylation, pluripotency gene expression and proliferation, with G1 pileup. Setd1b overexpression could not rescue the proliferation defects caused by loss of Setd1a in embryonic stem cells. The precise developmental requirement for Setd1a suggests that gastrulation is regulated by a switch between the major H3K4 methyltransferases.