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.

Statins are common drugs that are clinically used to reduce elevated plasma cholesterol levels. Based on their solubility, statins are considered to be either hydrophilic or lipophilic. Amongst them, simvastatin has the highest lipophilicity to facilitate its ability to cross the blood-brain barrier. Recent studies have suggested that simvastatin could be a promising therapeutic option for different brain complications and diseases ranging from brain tumors (i.e., medulloblastoma and glioblastoma) to neurological disorders (i.e., Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease). Specific mechanisms of disease amelioration, however, are still unclear. Independent studies suggest that simvastatin may reduce the risk of developing certain neurodegenerative disorders. Meanwhile, other studies point towards inducing cell death in brain tumor cell lines. In this review, we outline the potential therapeutic effects of simvastatin on brain complications and review the clinically relevant molecular mechanisms in different cases.

Methyl CpG binding protein 2 (MeCP2) is an epigenetic reader that binds to methylated CpG dinucleotides and regulates gene transcription. Mecp2/MECP2 gene has 4 exons, encoding for protein isoforms MeCP2E1 and MeCP2E2. MeCP2 plays key roles in neurodevelopment, therefore, its gain- and loss-of-function mutations lead to neurodevelopmental disorders including Rett Syndrome. Here, we describe the structure, functional domains, and evidence support for potential additional alternatively spliced MECP2 transcripts and protein isoforms. We conclude that NCBI MeCP2 isoforms 3 and 4 contain certain MeCP2 functional domains. Our in silico analysis led to identification of histone modification and accessibility profiles at the MECP2 gene and its cis-regulatory elements. We conclude that the human MECP2 gene associated histone post-translational modifications exhibit high similarity between males and females. Between brain regions, histone modifications were found to be less conserved and enriched within larger genomic segments named as “S1–S11”. We also identified highly conserved DNA accessibility regions in different tissues and brain regions, named as “A1–A9” and “B1–B9”. DNA methylation profile was similar between mid-frontal gyrus of donors 35 days–25 years of age. Based on ATAC-seq data, the identified hypomethylated regions “H1–H8” intersected with most regions of the accessible chromatin (A regions).