MeCP2 Suppresses Nuclear MicroRNA Processing and Dendritic Growth by Regulating the DGCR8/Drosha Complex
MeCP2 Suppresses Nuclear MicroRNA Processing and Dendritic Growth by Regulating the DGCR8/Drosha Complex
复制标题
DOI：
10.1016/j.devcel.2014.01.032
复制
发表时间：
2014-03-10
影响因子：
11.8
通讯作者：
Qiu, Zilong
中科院分区：
文献类型：
--
作者：
Cheng, Tian-Lin;Wang, Zhizhi;Qiu, Zilong
X连锁基因MECP2（甲基-CpG结合蛋白2）的功能丧失和获得突变导致人类严重的神经发育障碍，如Rett综合征（RTT）和自闭症。MeCP2以前被认为是一种转录抑制因子，通过与甲基化DNA结合并募集组蛋白脱乙酰酶复合物（HDAC）。在这里，我们报告说，MeCP2调节基因表达转录后抑制核microRNA加工。我们发现MeCP2直接结合到DiGeorge综合征关键区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microRNA的蛋白质靶点包括CREB、LIMK 1和Pumilio2，它们在神经发育中起着关键作用。MeCP2功能的获得强烈抑制树突和棘的生长，这取决于MeCP2和DGCR8的相互作用。因此，通过与DGCR8直接相互作用控制microRNA加工代表了MeCP2调节基因表达和神经发育的机制。
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.