An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation
An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation
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DOI：
10.1038/nature04021
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发表时间：
2005-09-15
期刊：
影响因子：
64.8
通讯作者：
Shiekhattar, R
中科院分区：
文献类型：
--
作者：
Lee, MG;Wynder, C;Shiekhattar, R
我们之前已经描述了一种称为BHC或BRAF - HDAC复合物的多蛋白复合物，它是抑制神经元特异性基因所必需的(1)。我们已经证明BHC复合体被神经元沉默因子REST （re1沉默转录因子）招募，并介导REST应答基因的抑制1。BHC是由两种酶活性组成的多蛋白复合物：组蛋白去乙酰化酶（HDAC1或2）和最近描述的组蛋白去甲基化酶（BHC110，也称为LSD1或AOF2）（1-3）。在这里，我们发现含有BHC110的复合物显示与重组BHC110相比，组蛋白H3赖氨酸4 （H3K4）的去甲基化增加了近五倍。此外，重组BHC110不能使核小体上的H3K4去甲基化，但含有BHC110的复合物容易使核小体去甲基化。利用重组亚基体外重建BHC复合物揭示了REST协抑制因子CoREST的重要作用，它不仅刺激核心组蛋白的去甲基化，还促进核小体底物的去甲基化。我们发现核小体去甲基化是CoREST增强BHC110和核小体之间关联的结果。体内细胞培养中CoREST的缺失导致rest应答基因表达的去抑制和H3K4甲基化的增加。总之，这些结果突出了CoREST在体外和体内H3K4去甲基化中的重要作用。
We have previously described a multiprotein complex termed the BHC or BRAF - HDAC complex, which is required for the repression of neuronal-specific genes(1). We have shown that the BHC complex is recruited by a neuronal silencer, REST (RE1-silencing transcription factor), and mediates the repression of REST-responsive genes1. BHC is a multiprotein complex consisting of two enzymatic activities: a histone deacetylase (HDAC1 or 2) and a recently described histone demethylase (BHC110, also known as LSD1 or AOF2)(1-3). Here we show that BHC110-containing complexes show a nearly fivefold increase in demethylation of histone H3 lysine 4 (H3K4) compared to recombinant BHC110. Furthermore, recombinant BHC110 is unable to demethylate H3K4 on nucleosomes, but BHC110-containing complexes readily demethylate nucleosomes. In vitro reconstitution of the BHC complex using recombinant subunits reveals an essential role for the REST corepressor CoREST, not only in stimulating demethylation on core histones but also promoting demethylation of nucleosomal substrates. We find that nucleosomal demethylation is the result of CoREST enhancing the association between BHC110 and nucleosomes. Depletion of CoREST in in vivo cell culture results in de-repression of REST-responsive gene expression and increased methylation of H3K4. Together, these results highlight an essential role for CoREST in demethylation of H3K4 both in vitro and in vivo.