Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells.
Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells.
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DOI：
10.1016/j.cell.2011.11.054
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发表时间：
2011-12-23
期刊：
影响因子：
64.5
通讯作者：
Fazzio TG
中科院分区：
文献类型：
--
作者：
Yildirim O;Li R;Hung JH;Chen PB;Dong X;Ee LS;Weng Z;Rando OJ;Fazzio TG
胚胎干细胞的自我更新和多能性需要许多染色质调节因子，但很少有详细的研究。在这里，我们研究了几种染色质调节因子的作用，它们的缺失会影响胚胎干细胞的多能状态。我们发现Mbd3和Brg1通过调节启动子核小体占用来拮抗调节一组共同的基因。此外，Mbd3和Brg1在5-羟甲基胞嘧啶（5hmC）的生物学中发挥着关键作用：Mbd3在体内与Tet1和5hmC共定位，Mbd3敲低优先影响5hmC标记基因的表达，Mbd3定位依赖于Tet1， Mbd3在体外相对于5-甲基胞嘧啶优先结合5hmC。最后，Mbd3和Brg1本身也是体内正常水平5hmC所必需的。总之，我们的研究结果确定了5hmC的效应，并揭示了拮抗染色质调节剂对基因表达的控制是胚胎干细胞中令人惊讶的常见调控策略。
Numerous chromatin regulators are required for embryonic stem (ES) cell self-renewal and pluripotency, but few have been studied in detail. Here, we examine the roles of several chromatin regulators whose loss affects the pluripotent state of ES cells. We find that Mbd3 and Brg1 antagonistically regulate a common set of genes by regulating promoter nucleosome occupancy. Furthermore, both Mbd3 and Brg1 play key roles in the biology of 5-hydroxymethylcytosine (5hmC): Mbd3 co-localizes with Tet1 and 5hmC in vivo, Mbd3 knockdown preferentially affects expression of 5hmC-marked genes, Mbd3 localization is Tet1-dependent, and Mbd3 preferentially binds to 5hmC relative to 5-methylcytosine in vitro. Finally, both Mbd3 and Brg1 are themselves required for normal levels of 5hmC in vivo. Together, our results identify an effector for 5hmC, and reveal that control of gene expression by antagonistic chromatin regulators is a surprisingly common regulatory strategy in ES cells.
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