Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development
Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development
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DOI：
10.1242/dev.082198
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发表时间：
2012-10-15
期刊：
影响因子：
4.6
通讯作者：
Kageyama, Ryoichiro
中科院分区：
文献类型：
--
作者：
Tan, Siok-Lay;Nishi, Miyuki;Kageyama, Ryoichiro
在发育中的大脑中，神经祖细胞通过改变基因表达谱来切换分化能力，这些基因表达谱部分受表观遗传控制（如组蛋白修饰）的控制，尽管确切的机制尚不清楚。在这里，我们发现ESET（Setdb1），一种组蛋白H3 Lys9（H3K9）甲基转移酶，在小鼠大脑发育的早期阶段高度表达，但随着时间的推移下调，ESET的消融导致H3K9三甲基化减少和基因的错误调节，导致严重的大脑缺陷和早期死亡。在突变体脑中，内源性逆转录转座子被去抑制，非神经基因表达被激活。此外，早期神经发生严重受损，而星形胶质细胞形成增强。我们的结论是，有一个表观遗传作用的ESET在时间和组织特异性基因表达，导致在适当的控制大脑发育。
In the developing brain, neural progenitor cells switch differentiation competency by changing gene expression profiles that are governed partly by epigenetic control, such as histone modification, although the precise mechanism is unknown. Here we found that ESET (Setdb1), a histone H3 Lys9 (H3K9) methyltransferase, is highly expressed at early stages of mouse brain development but downregulated over time, and that ablation of ESET leads to decreased H3K9 trimethylation and the misregulation of genes, resulting in severe brain defects and early lethality. In the mutant brain, endogenous retrotransposons were derepressed and non-neural gene expression was activated. Furthermore, early neurogenesis was severely impaired, whereas astrocyte formation was enhanced. We conclude that there is an epigenetic role of ESET in the temporal and tissue-specific gene expression that results in proper control of brain development.