The methyl-CpG-binding protein 2 (MECP2) is a critical global regulator of gene expression. Mutations in MECP2 cause neurodevelopmental disorders including Rett syndrome (RTT). MECP2 exon 2 is spliced into two alternative messenger ribonucleic acid (mRNA) isoforms encoding MECP2-E1 or MECP2-E2 protein isoforms that differ in their N-termini. MECP2-E2, isolated first, was used to define the general roles of MECP2 in methyl-deoxyribonucleic acid (DNA) binding, targeting of transcriptional regulatory complexes, and its disease-causing impact in RTT. It was later found that MECP2-E1 is the most abundant isoform in the brain and its exon 1 is also mutated in RTT. MECP2 transcripts undergo alternative polyadenylation generating mRNAs with four possible 3′untranslated region (UTR) lengths ranging from 130 to 8600 nt. Together, the exon and 3′UTR isoforms display remarkable abundance disparity across cell types and tissues during development. These findings indicate discrete means of regulation and suggest that protein isoforms perform non-overlapping roles. Multiple regulatory programs have been explored to explain these disparities. DNA methylation patterns of the MECP2 promoter and first intron impact MECP2-E1 and E2 isoform levels. Networks of microRNAs and RNA-binding proteins also post-transcriptionally regulate the stability and translation efficiency of MECP2 3′UTR isoforms. Finally, distinctions in biophysical properties in the N-termini between MECP2-E1 and E2 lead to variable protein stabilities and DNA binding dynamics. This review describes the steps taken from the discovery of MECP2, the description of its key functions, and its association with RTT, to the emergence of evidence revealing how MECP2 isoforms are differentially regulated at the transcriptional, post-transcriptional and post-translational levels.

中文翻译：

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MECP2 外显子和 3'UTR 异构体的调节、多样性和功能。

甲基-CpG结合蛋白 2 ( MECP2 ) 是基因表达的关键全局调节剂。MECP2 的突变会导致神经发育障碍，包括 Rett 综合征 (RTT)。MECP2外显子 2 被拼接成两个替代的信使核糖核酸 (mRNA) 异构体，编码 MECP2-E1 或 MECP2-E2 蛋白质异构体，它们的 N 末端不同。首先分离的 MECP2-E2 用于定义 MECP2 在甲基-脱氧核糖核酸 (DNA) 结合、转录调控复合物的靶向及其在 RTT 中引起疾病​​的影响中的一般作用。后来发现MECP2-E1是大脑中最丰富的同种型，其外显子 1 在 RTT 中也发生了突变。MECP2转录物经历替代多聚腺苷酸化生成 mRNA，具有四种可能的 3' 非翻译区 (UTR) 长度，范围从 130 到 8600 nt。总之，外显子和 3'UTR 亚型在发育过程中在细胞类型和组织之间显示出显着的丰度差异。这些发现表明调节的离散方式并表明蛋白质同种型发挥非重叠作用。已经探索了多个监管计划来解释这些差异。MECP2启动子和第一个内含子的DNA 甲基化模式影响 MECP2-E1 和 E2 亚型水平。microRNA 和 RNA 结合蛋白的网络也在转录后调节MECP2的稳定性和翻译效率3'UTR 异构体。最后，MECP2-E1 和 E2 之间 N 端生物物理特性的差异导致可变的蛋白质稳定性和 DNA 结合动力学。这篇综述描述了从 MECP2 的发现、其关键功能的描述及其与 RTT 的关联，到揭示MECP2同种型如何在转录、转录后和翻译后水平上差异调节的证据的出现所采取的步骤。