Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p
Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p
复制标题
DOI：
10.1101/gad.207456.112
复制
发表时间：
2013-03-01
影响因子：
10.5
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Han, Kihoon;Gennarino, Vincenzo Alessandro;Zoghbi, Huda Y.
人类正常的神经功能需要精确控制表观遗传调节因子甲基CpG结合蛋白2（MeCP 2）的水平。MeCP 2蛋白水平在胎儿脑中较低，其中主要的MECP 2转录物具有异常长的39个非翻译区（UTR）。在这里，我们表明，miR-483- 5 p，印迹IGF 2的基因内microRNA，通过MECP 2长39 UTR中的人类特异性结合位点调节MeCP 2水平。我们证明了miR-483- 5 p和MeCP 2水平在发育中的人脑和来自Beckwith-Wiedemann综合征患者的成纤维细胞中的负相关性。重要的是，miR-483- 5 p的表达挽救了过表达人MeCP 2的神经元的异常树突棘表型。此外，miR-483- 5 p调节MeCP 2相互作用辅阻遏物复合物的蛋白质水平，包括HDAC 4和TBL 1X。这些数据提供了对miR-483- 5 p在人类胎儿发育过程中调节MeCP 2和相互作用蛋白水平的作用的深入了解。
Proper neurological function in humans requires precise control of levels of the epigenetic regulator methyl CpG-binding protein 2 (MeCP2). MeCP2 protein levels are low in fetal brains, where the predominant MECP2 transcripts have an unusually long 39 untranslated region (UTR). Here, we show that miR-483-5p, an intragenic microRNA of the imprinted IGF2, regulates MeCP2 levels through a human-specific binding site in the MECP2 long 39 UTR. We demonstrate the inverse correlation of miR-483-5p and MeCP2 levels in developing human brains and fibroblasts from Beckwith-Wiedemann syndrome patients. Importantly, expression of miR-483-5p rescues abnormal dendritic spine phenotype of neurons overexpressing human MeCP2. In addition, miR-483-5p modulates the levels of proteins of the MeCP2-interacting corepressor complexes, including HDAC4 and TBL1X. These data provide insight into the role of miR-483-5p in regulating the levels of MeCP2 and interacting proteins during human fetal development.