Reciprocal regulation of autism-related genes MeCP2 and PTEN via microRNAs.
Reciprocal regulation of autism-related genes MeCP2 and PTEN via microRNAs.
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通过 microRNA 相互调节自闭症相关基因 MeCP2 和 PTEN
DOI：
10.1038/srep20392
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发表时间：
2016-02-04
影响因子：
4.6
通讯作者：
Zhou WH
中科院分区：
文献类型：
--
作者：
Lyu JW;Yuan B;Cheng TL;Qiu ZL;Zhou WH
MeCP 2编码甲基CpG结合蛋白，其在抑制基因表达中起关键作用，其突变导致Rett综合征和自闭症。PTEN是一种重要的肿瘤抑制基因，其在人类癌症和自闭症谱系障碍中频繁突变。各种研究表明，MeCP 2和PTEN蛋白在大脑发育中发挥重要作用。在这里，我们发现MeCP 2和PTEN β通过microRNA相互调节表达。MeCP 2的敲低导致microRNA-137的上调，其反过来抑制PTEN的表达，因此当MeCP 2被敲低时，PTEN将被下调。此外，我们发现PTEN的缺失导致CREB的Serine 133磷酸化，从而增加microRNA-132的表达。miR-132通过靶向MeCP 2 mRNA的3′UTR抑制MeCP 2的表达。我们的工作表明，两个关键疾病相关基因MeCP 2和PTEN β通过不同的机制相互调节表达，这表明各种疾病中的罕见突变可能导致其他关键基因的失调并产生意想不到的后果。
MeCP2encodes a methyl-CpG-binding protein that plays a critical role in repressing gene expression, mutations of which lead to Rett syndrome and autism.PTENis a critical tumor suppressor gene that is frequently mutated in human cancers and autism spectrum disorders. Various studies have shown that both MeCP2 and PTEN proteins play important roles in brain development. Here we find that MeCP2 and PTEN reciprocally regulate expression of each other via microRNAs. Knockdown of MeCP2 leads to upregulation of microRNA-137, which in turn represses expression of PTEN, thus PTEN would be down-regulated when MeCP2 is knockdown. Furthermore, we find that deletion of PTEN leads to phosphorylation of Serine 133 of CREB, then increases the expression of microRNA-132. miR-132 inhibits the expression of MeCP2 by targeting on the 3′UTR of MeCP2 mRNA. Our work shows that two critical disorders-related gene MeCP2 and PTEN reciprocally regulate expression of each other by distinct mechanisms, suggesting that rare mutations in various disorders may lead to dysregulation of other critical genes and yield unexpected consequences.