Good Katrina V, Vincent John B, Ausió Juan
Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
Molecular Neuropsychiatry & Development (MiND) Lab, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
Front Genet. 2021 Jan 21;12:620859. doi: 10.3389/fgene.2021.620859. eCollection 2021.
Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.
甲基 CpG 结合蛋白 2（MeCP2）的突变是雷特综合征（RTT）的主要病因，雷特综合征是一种罕见的神经发育障碍，在最初看似正常的发育之后会出现一段明显的发育倒退期。此类 MeCP2 改变通常会导致 DNA 结合和染色质聚集能力的变化，以及该蛋白的稳定性变化。在其他功能中，MeCP2 与甲基化的基因组 DNA 结合，甲基化是一种重要的表观遗传标记，具有广泛的生理意义，包括神经元发育。在本综述中，我们将总结雷特综合征背后的遗传基础，以及 MeCP2 及其突变版本所表现出的不同程度的蛋白质稳定性。此外，还将探讨 MeCP2 与 mRNA 剪接、miRNA 加工及其他非编码 RNA（ncRNA）之间过去和新出现的关系，我们认为这些分子可能是理解这种重要染色质修饰因子基因缺失所带来的表观遗传后果的关键环节。重要的是，尽管 MeCP2 在大脑中高度表达且在大脑中得到了最广泛的研究，但该蛋白及其改变在其他组织中的作用也不能被忽视，我们也将对此进行讨论。最后，将描述由两种 MeCP2 异构体（MeCP2-E1 和 MeCP2-E2）的结构和功能影响给雷特综合征病理学带来的额外复杂性。表观遗传疗法在临床上越来越受欢迎，但雷特综合征的治疗比单纯的表观遗传疾病预期的要复杂，这在未来的临床背景中应予以考虑。
