Eed/Sox2 regulatory loop controls ES cell self‐renewal through histone methylation and acetylation
Eed/Sox2 regulatory loop controls ES cell self‐renewal through histone methylation and acetylation
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DOI：
10.1038/emboj.2011.126
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发表时间：
2011-06
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影响因子：
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通讯作者：
Hiroki Ura;K. Murakami;T. Akagi;K. Kinoshita;S. Yamaguchi;S. Masui;H. Niwa;H. Koide;T. Yokota
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文献类型：
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作者：
Hiroki Ura;K. Murakami;T. Akagi;K. Kinoshita;S. Yamaguchi;S. Masui;H. Niwa;H. Koide;T. Yokota
转录因子和表观遗传调节剂参与胚胎干细胞（ES）自我更新的维持。在这里，我们证明了在ES细胞中Sox 2（一种自我更新不可或缺的转录因子）和胚胎外胚层发育（Eed）（一种调节组蛋白甲基化的表观遗传调节剂）之间存在一个调节环。我们发现Sox 2和Eed正调控彼此的表达。有趣的是，Sox 2过表达抑制了Eed缺陷ES细胞中分化相关基因的诱导，而没有恢复组蛋白甲基化。通过敲低组蛋白乙酰转移酶（HAT）、Tip 60或Elp 3和Sox 2刺激这些HAT的表达，可以阻止这种Sox 2介导的抑制。此外，任一HAT的强制表达导致Eed缺陷细胞中分化相关基因的抑制。这些结果表明，Sox 2通过促进组蛋白乙酰化克服Eed缺陷ES细胞的表型。我们还发现，敲除Eed和敲低这些HAT协同增强了ES细胞中分化相关基因的上调。综上所述，我们的研究结果表明，Eed/Sox 2调节环通过控制组蛋白甲基化和乙酰化来维持ES细胞的自我更新。
Transcription factors and epigenetic modulators are involved in the maintenance of self‐renewal in embryonic stem (ES) cells. Here, we demonstrate the existence of a regulatory loop in ES cells between Sox2, an indispensable transcription factor for self‐renewal, and embryonic ectoderm development (Eed), an epigenetic modulator regulating histone methylation. We found that Sox2 and Eed positively regulate each other's expression. Interestingly,Sox2overexpression suppressed the induction of differentiation‐associated genes inEed‐deficient ES cells without restoring histone methylation. This Sox2‐mediated suppression was prevented by knockdown of the histone acetyltransferase (HAT),Tip60orElp3, and Sox2 stimulated expression of these HATs. Furthermore, forced expression of either HAT resulted in repression of differentiation‐associated genes inEed‐deficient cells. These results suggest that Sox2 overcame the phenotype ofEed‐deficient ES cells by promoting histone acetylation. We also found that knockout of Eed and knockdown of these HATs synergistically enhanced the upregulation of differentiation‐associated genes in ES cells. Taken together, our results suggest that the Eed/Sox2 regulatory loop contributes to the maintenance of self‐renewal in ES cells by controlling histone methylation and acetylation.