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首页> 外文期刊>Nature >The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation
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The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation

机译：组蛋白H3K4脱甲基酶SMCX将REST目标基因与X连锁性智力低下联系起来

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摘要

Gene transcription is critically influenced by chromatin structure and the modification status of histone tails. Methylation of lysine residues in histone tails is dynamically regulated by the opposing activities of histone methyltransferases and histone demethylases. Here we show that JARID1C/SMCX, a JmjC-domain-containing protein implicated in X-linked mental retardation and epilepsy, possesses H3K4 tri-demethylase activity and functions as a transcriptional repressor. An SMCX complex isolated from HeLa cells contains additional chromatin modifiers (the histone deacetylases HDAC1 and HDAC2, and the histone H3K9 methyltransferase G9a) and the transcriptional repressor REST, suggesting a direct role for SMCX in chromatin dynamics and REST-mediated repression. Chromatin immuno-precipitation reveals that SMCX and REST co-occupy the neuron-restrictive silencing elements in the promoters of a subset of REST target genes. RNA-interference-mediated depletion of SMCX derepresses several of these targets and simultaneously increases H3K4 trimethylation at the sodium channel type 2A (SCN2A) and synapsin Ⅰ (SYN1) promoters. We propose that loss of SMCX activity impairs REST-mediated neuronal gene regulation, thereby contributing to SMCX-associated X-linked mental retardation.
机译：基因转录受到染色质结构和组蛋白尾部修饰状态的严重影响。组蛋白尾巴中赖氨酸残基的甲基化由组蛋白甲基转移酶和组蛋白脱甲基酶的相反活性动态调节。在这里，我们显示JARID1C / SMCX是一种包含JmjC域的蛋白质，与X连锁的智力低下和癫痫症有关，具有H3K4三脱甲基酶活性，并起着转录抑制因子的作用。从HeLa细胞中分离的SMCX复合物包含其他染色质修饰剂（组蛋白脱乙酰基酶HDAC1和HDAC2，以及组蛋白H3K9甲基转移酶G9a）和转录阻遏物REST，表明SMCX在染色质动力学和REST介导的阻遏中具有直接作用。染色质的免疫沉淀表明，SMCX和REST共同占据了REST目标基因子集的启动子中的神经元限制性沉默元件。 RNA干扰介导的SMCX耗竭可抑制其中的几个靶点，并同时增加钠通道2A（SCN2A）和突触素Ⅰ（SYN1）启动子上的H3K4三甲基化。我们提出，SMCX活性的丧失会损害REST介导的神经元基因调节，从而促进SMCX相关的X连锁性智力低下。

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