MeCP2 通过调控 DGCR8/Drosha 复合物抑制核微小 RNA 的加工和树突生长。

MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex.

机构信息

Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.

出版信息

Dev Cell. 2014 Mar 10;28(5):547-60. doi: 10.1016/j.devcel.2014.01.032.

DOI:10.1016/j.devcel.2014.01.032

PMID:24636259

Abstract

Loss- and gain-of-function mutations of the X-linked gene MECP2 (methyl-CpG binding protein 2) lead to severe neurodevelopmental disorders in humans, such as Rett syndrome (RTT) and autism. MeCP2 is previously known as a transcriptional repressor by binding to methylated DNA and recruiting histone deacetylase complex (HDAC). Here, we report that MeCP2 regulates gene expression posttranscriptionally by suppressing nuclear microRNA processing. We found that MeCP2 binds directly to DiGeorge syndrome critical region 8 (DGCR8), a critical component of the nuclear microRNA-processing machinery, and interferes with the assembly of Drosha and DGCR8 complex. Protein targets of MeCP2-suppressed microRNAs include CREB, LIMK1, and Pumilio2, which play critical roles in neural development. Gain of function of MeCP2 strongly inhibits dendritic and spine growth, which depends on the interaction of MeCP2 and DGCR8. Thus, control of microRNA processing via direct interaction with DGCR8 represents a mechanism for MeCP2 regulation of gene expression and neural development.

摘要

X 连锁基因 MECP2（甲基-CpG 结合蛋白 2）的功能获得和功能丧失突变导致人类严重的神经发育障碍，如雷特综合征（RTT）和自闭症。MeCP2 先前被认为是一种通过与甲基化 DNA 结合并募集组蛋白去乙酰化酶复合物（HDAC）的转录抑制剂。在这里，我们报告 MeCP2 通过抑制核 microRNA 加工来进行转录后基因表达调控。我们发现 MeCP2 直接结合到 DiGeorge 综合征关键区域 8（DGCR8），这是核 microRNA 加工机制的关键组成部分，并干扰 Drosha 和 DGCR8 复合物的组装。MeCP2 抑制的 microRNA 的蛋白质靶标包括 CREB、LIMK1 和 Pumilio2，它们在神经发育中发挥关键作用。MeCP2 的功能获得强烈抑制树突和棘突的生长，这取决于 MeCP2 和 DGCR8 的相互作用。因此，通过与 DGCR8 的直接相互作用来控制 microRNA 加工代表了 MeCP2 调节基因表达和神经发育的一种机制。