Antithetic effects of MBD2a on gene regulation
Antithetic effects of MBD2a on gene regulation
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DOI：
10.1128/mcb.23.8.2645-2657.2003
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发表时间：
2003-04-01
影响因子：
5.3
通讯作者：
Nakajima, T
中科院分区：
文献类型：
--
作者：
Fujita, H;Fujii, R;Nakajima, T
DNA甲基化对于发育过程中的表观遗传基因调控至关重要。环腺苷酸（cAMP）反应元件（CRE）存在于许多cAMP调控基因的启动子中，在基因表达中起重要作用。甲基化发生在CRE位点上，并通过直接机制导致转录抑制，即甲基阻止cAMP反应因子CREB与该位点的结合。最近的一项研究表明，核小体在抑制转录方面也很重要。在这项研究中，我们研究了甲基化CRE的转录抑制的调节。我们主要研究甲基化CpG结合域蛋白2（MBD 2）。MBD 2由MBD 2a和MBD 2b两种形式组成，后者缺乏MBD 2a的N-末端延伸。出乎意料的是，我们发现MBD 2a，而不是MBD 2b，促进了未甲基化cAMP反应基因的激活。体内结合试验表明，MBD 2a选择性地与RNA解旋酶A（RHA），CREB转录辅激活因子复合物的一个组成部分相互作用。MBD 2a和RHA协同增强CREB依赖性基因表达。有趣的是，免疫共沉淀试验表明MBD 2a与RHA的结合与组蛋白去乙酰化酶1无关。我们的研究结果表明MBD 2a在基因调控中的新作用。
DNA methylation is essential for epigenetic gene regulation during development. The cyclic AMP (cAMP)responsive element (CRE) is found in the promoter of many cAMP-regulated genes and plays important roles in their gene expression. Methylation occurs on the CRE site and results in transcriptional repression via a direct mechanism, that is, prevention by the methyl group of binding of the cAMP-responsive factor CREB to this site. A recent study indicated that the nucleosome is also important in repressing transcription. In this study, we investigated the regulation of transcriptional repression on methylated CRE. We focused on methyl-CpG binding domain protein 2 (MBD2). MBD2 consists of two forms, MBD2a and MBD2b, the latter lacking the N-terminal extension of MBD2a. Unexpectedly, we found that MBD2a, but not MBD2b, promoted activation of the unmethylated cAMP-responsive genes. An in vivo binding assay revealed that MBD2a selectively interacted with RNA helicase A (RHA), a component of CREB transcriptional coactivator complexes. MBD2a and RHA cooperatively enhanced CREB-dependent gene expression. Interestingly, coimmunoprecipitation assays demonstrated that MBD2a binding to RHA was not associated with histone deacetylase 1. Our results indicate a novel role for MBD2a in gene regulation.