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

Abstract

DNA methylation, one of the most well-studied epigenetic modifications, is involved in a wide spectrum of biological processes. Epigenetic mechanisms control cellular morphology and function. Such regulatory mechanisms involve histone modifications, chromatin remodeling, DNA methylation, non-coding regulatory RNA molecules, and RNA modifications. One of the most well-studied epigenetic modifications is DNA methylation that plays key roles in development, health, and disease. Our brain is probably the most complex part of our body, with a high level of DNA methylation. A key protein that binds to different types of methylated DNA in the brain is the methyl-CpG binding protein 2 (MeCP2). MeCP2 acts in a dose-dependent manner and its abnormally high or low expression level, deregulation, and/or genetic mutations lead to neurodevelopmental disorders and aberrant brain function. Recently, some of MeCP2-associated neurodevelopmental disorders have emerged as neurometabolic disorders, suggesting a role for MeCP2 in brain metabolism. Of note, MECP2 loss-of-function mutation in Rett Syndrome is reported to cause impairment of glucose and cholesterol metabolism in human patients and/or mouse models of disease. The purpose of this review is to outline the metabolic abnormalities in MeCP2-associated neurodevelopmental disorders that currently have no available cure. We aim to provide an updated overview into the role of metabolic defects associated with MeCP2-mediated cellular function for consideration of future therapeutic strategies.

BDNF Modulation by microRNAs: An Update on the Experimental Evidence

“…A compensatory increase in CREB activity following a decrease in the concentrations of BDNF and methyl CpG binding protein 2 (MeCP2) was evidenced in the brain of 132/212 KO mice (Hernandez-Rapp et al, 2015;Klein et al, 2007). While MeCP2 is a nuclear protein that may function as both a transcriptional activator or repressor, it works as a stabilizer of BDNF expression patterns and cell homeostasis (Buist et al, 2021;Pejhan et al, 2020;Vuu et al, 2023). Another compensatory effect is seen for BDNF in dendritogenesis when inhibition of miR-15a, and the consequent relief of BDNF supression, can rescue dendritic maturation deficits in MeCP2-deficient neurons (Y.…”

Central Causation of Autism/ASDs via Excessive [Ca2+]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations

“…Each of the six mechanisms that regulate synaptogenesis have been shown to be abnormal in autism/ASD patients: neuronal migration [36][37][38][39], dendritic outgrowth [10,40,41], synapse formation [8,10,15,42], synaptic maturation [8,42], synaptic pruning [8,15,43,44], and MeCP2 function [45][46][47][48]. Qiu and Cheng [48] linked changed MeCP2 function with increased ubiquitination and degradation of synaptic proteins, suggesting a plausible role of lowered MeCP2 function in producing increased synaptic pruning in ASDs.…”

The Potential Therapeutic Application of Simvastatin for Brain Complications and Mechanisms of Action

“…On the contrary to the extrahepatic tissues, brain cholesterol is exclusively synthesized from local de novo synthesis, which takes place in both neurons and astrocytes. During neurodevelopment, neurons produce a higher level of cholesterol than astrocytes, suggesting that the developing neurons are dependent on endogenous cholesterol synthesis [ 57 , 58 ]. However, in adult human brains, astrocytes mainly produce cholesterol in small amounts, as the elimination half-life of the cholesterol content of the human brain is estimated to be around 5 years [ 14 ].…”

“…In the Daoy Shh MB cells, simvastatin was also tested regarding the regulation of the methyl CpG-binding protein 2 ( MECP2 ) gene [ 106 ]. The encoded MeCP2 protein is an epigenetic factor [ 185 , 186 ], with specific involvement in gene transcription, brain metabolism, and neurodevelopmental disorders, including Rett Syndrome [ 58 , 187 , 188 , 189 , 190 , 191 , 192 ]. However, more recently, MeCP2 has been reported to have oncogenic properties in certain types of human cancer [ 193 ].…”