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首页> 外文期刊>Epigenetics & Chromatin >MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2
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MeCP2-E1 isoform is a dynamically expressed, weakly DNA-bound protein with different protein and DNA interactions compared to MeCP2-E2

机译：MeCP2-E1同工型是一种动态表达的，弱结合DNA的蛋白质，与MeCP2-E2相比具有不同的蛋白质和DNA相互作用

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MeCP2—a chromatin-binding protein associated with Rett syndrome—has two main isoforms, MeCP2-E1 and MeCP2-E2, differing in a few N-terminal amino acid residues. Previous studies have shown brain region-specific expression of these isoforms which, in addition to their different cellular localization and differential expression during brain development, suggest that they may also have non-overlapping molecular mechanisms. However, differential functions of MeCP2-E1 and E2 remain largely unexplored. Here, we show that the N-terminal domains (NTD) of MeCP2-E1 and E2 modulate the ability of the methyl-binding domain (MBD) to interact with DNA as well as influencing the turn-over rates, binding dynamics, response to neuronal depolarization, and circadian oscillations of the two isoforms. Our proteomics data indicate that both isoforms exhibit unique interacting protein partners. Moreover, genome-wide analysis using ChIP-seq provide evidence for a shared as well as a specific regulation of different sets of genes. Our study supports the idea that Rett syndrome might arise from simultaneous impairment of cellular processes involving non-overlapping functions of MECP2 isoforms. For instance, MeCP2-E1 mutations might impact stimuli-dependent chromatin regulation, while MeCP2-E2 mutations could result in aberrant ribosomal expression. Overall, our findings provide insight into the functional complexity of MeCP2 by dissecting differential aspects of its two isoforms.
机译：MeCP2是一种与Rett综合征相关的染色质结合蛋白，具有两种主要的亚型，即MeCP2-E1和MeCP2-E2，它们的N端氨基酸残基有所不同。先前的研究表明这些同工型在大脑区域的特异性表达，除了它们在大脑发育过程中的不同细胞定位和差异表达外，还表明它们也可能具有不重叠的分子机制。但是，MeCP2-E1和E2的差分功能在很大程度上仍未开发。在这里，我们显示MeCP2-E1和E2的N末端结构域（NTD）调节甲基结合结构域（MBD）与DNA相互作用的能力，并影响周转率，结合动力学，对神经元去极化和两个亚型的昼夜节律振荡。我们的蛋白质组学数据表明，两种同工型均表现出独特的相互作用蛋白伴侣。此外，使用ChIP-seq进行全基因组分析可为不同基因集的共享调控和特定调控提供证据。我们的研究支持以下观点：Rett综合征可能是由涉及MECP2亚型的非重叠功能的细胞过程同时受损引起的。例如，MeCP2-E1突变可能会影响刺激依赖的染色质调节，而MeCP2-E2突变可能导致异常的核糖体表达。总体而言，我们的发现通过剖析MeCP2两种同工型的不同方面，提供了对MeCP2功能复杂性的了解。

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