4.5 Review

MeCP2 ubiquitination and sumoylation, in search of a function

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Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway

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Summary: This study found that exercise can change lactylation modification, inhibiting the progression of atherosclerotic cardiovascular disease (ASCVD). Exercise training promotes lactylation of the Mecp2 protein, reducing the expression of vascular cell adhesion molecules, cytokines, and increasing the level of endothelial nitric oxide synthase. Mechanistically, lactylation represses the expression of epiregulin, affecting the MAPK signaling pathway and promoting the regression of atherosclerosis. This study provides new insights into the anti-atherosclerotic effects of exercise-induced post-translational modification (PTM).

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MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism

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Summary: DNA methylation is a well-studied epigenetic modification involved in various biological processes, including cellular morphology and function control. MeCP2, a key protein binding to methylated DNA in the brain, plays a crucial role in neurodevelopmental disorders and aberrant brain function. Recently, MeCP2-associated neurodevelopmental disorders have been linked to neurometabolic abnormalities, suggesting the involvement of MeCP2 in brain metabolism. This review aims to outline the metabolic defects in MeCP2-associated neurodevelopmental disorders and provide an updated overview for future therapeutic strategies.

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Multiscale Computational Study of the Conformation of the Full-Length Intrinsically Disordered Protein MeCP2

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Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders

Jian Zhou et al.

Summary: MeCP2 plays a critical role in Rett syndrome and MECP2 duplication syndrome. It interacts with a transcription factor, TCF20, at the chromatin interface, and together they regulate the expression of neuronal genes. Reduction of TCF20 partially rescues the behavioral deficits caused by MECP2 overexpression. A patient with a mutation in the PHF14 subunit of the TCF20 complex, disrupting the MeCP2-PHF14-TCF20 interaction, exhibits Rett-like neurological features.

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Profiling beneficial and potential adverse effects of MeCP2 overexpression in a hypomorphic Rett syndrome mouse model

Sheryl Anne D. Vermudez et al.

Summary: This study found that introducing a wild-type MECP2 transgene in a RTT mouse model can reverse most RTT-like phenotypes, but may have adverse effects in some cases due to the hypomorphic R133C mutation. The results suggest that personalized approaches may be important for evaluating the safety and efficacy of MeCP2-targeted therapies.

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Mosaicism of common pathogenic MECP2 variants identified in two males with a clinical diagnosis of Rett syndrome

Jessica A. Cooley Coleman et al.

Summary: This study identified mosaic variants in the MECP2 gene in two male patients with classic RTT syndrome, leading to a lengthy diagnostic journey. The study found surprisingly similar results in mosaic variant fraction using different technologies, emphasizing the importance of somatic mosaicism in diagnosis.

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MeCP2 and transcriptional control of eukaryotic gene expression

Ghanan Bin Akhtar et al.

Summary: Eukaryotic gene expression is regulated by multiple steps, which work together to maintain cellular morphology and function properly. The methyl-CpG-binding protein 2 (MeCP2) is a well-studied multifunctional factor that plays a critical role in maintaining the accurate gene expression program of eukaryotic cells.

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A catalogue of 863 Rett-syndrome-causing MECP2 mutations and lessons learned from data integration

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Summary: Research on MECP2 in Rett syndrome can improve understanding of disease mechanisms and faster diagnosis of variants, but the lack of interoperability between genotype-phenotype databases currently hinders this process. Integrating a large amount of MECP2 variant data revealed variants that can cause both RTT and be benign, indicating additional factors contributing to disease development in these cases.

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Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations

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Ivo A. Hendriks et al.

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