MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion
MeCP2 is a microsatellite binding protein that protects CA repeats from nucleosome invasion
复制标题
DOI：
10.1126/science.abd5581
复制
发表时间：
2021-06-25
期刊：
影响因子：
56.9
通讯作者：
Hamiche, Ali
中科院分区：
文献类型：
--
作者：
Ibrahim, Abdulkhaleg;Papin, Christophe;Hamiche, Ali
Rett综合征蛋白MeCP2被描述为甲基CpG结合蛋白，但其确切功能尚不清楚。在这里，我们展示了小鼠MeCP2是一种微卫星结合蛋白，它特异性地识别羟甲基化的CA重复。MeCP2的缺失改变了CA重复序列和片层相关结构域的染色质组织，导致CA重复序列上的核小体聚集，并导致全基因组转录失调。MeCP2与羟甲基化CA重复序列形成的复合体的结构显示出一种特征的DNA形状，在5-羟甲基胞嘧啶的几何构型上有很大的改变，这是Arg(133)特异识别的，Arg(133)是一种关键残基，其突变导致Rett综合征。我们的工作发现MeCP2是一种微卫星DNA结合蛋白，它以5hmC修饰的富含CA的链为靶标，并保持基因组区域无核小体，表明MeCP2功能障碍在Rett综合征中发挥了作用。
The Rett syndrome protein MeCP2 was described as a methyl-CpG-binding protein, but its exact function remains unknown. Here we show that mouse MeCP2 is a microsatellite binding protein that specifically recognizes hydroxymethylated CA repeats. Depletion of MeCP2 alters chromatin organization of CA repeats and lamina-associated domains and results in nucleosome accumulation on CA repeats and genome-wide transcriptional dysregulation. The structure of MeCP2 in complex with a hydroxymethylated CA repeat reveals a characteristic DNA shape, with considerably modified geometry at the 5-hydroxymethylcytosine, which is recognized specifically by Arg(133), a key residue whose mutation causes Rett syndrome. Our work identifies MeCP2 as a microsatellite DNA binding protein that targets the 5hmC-modified CA-rich strand and maintains genome regions nucleosome-free, suggesting a role for MeCP2 dysfunction in Rett syndrome.