MeCP2: A Critical Regulator of Chromatin in Neurodevelopment and Adult Brain Function.

Kubra Gulmez Karaca,David V.C Brito,Ana M.M Oliveira

doi:10.3390/ijms20184577

Abstract

Methyl CpG binding protein 2 (MeCP2) was first identified as a nuclear protein with a transcriptional repressor role that recognizes DNA methylation marks. MeCP2 has a well-established function in neurodevelopment, as evidenced by the severe neurological impairments characteristic of the Rett syndrome (RTT) pathology and the MeCP2 duplication syndrome (MDS), caused by loss or gain of MeCP2 function, respectively. Research aimed at the underlying pathophysiological mechanisms of RTT and MDS has significantly advanced our understanding of MeCP2 functions in the nervous system. It has revealed, however, that MeCP2 has more varied and complex roles than previously thought. Here we review recent insights into the functions of MeCP2 in neurodevelopment and the less explored requirement for MeCP2 in adult brain function. We focus on the emerging view that MeCP2 is a global chromatin organizer. Finally, we discuss how the individual functions of MeCP2 in neurodevelopment and adulthood are linked to its role as a chromatin regulator.

Highlights

Methyl CpG binding protein 2 (MeCP2) is a member of a complex family of proteins, the methyl-CpG-binding domain (MBD) protein family, that bind to methylated cytosines
This study identified an interaction between MeCP2 and the transcription factor cAMP response element binding protein (CREB) and proposed that MeCP2 may function as a transcription activator through the interaction with transcription factors
Chromatin changes were shown to be accompanied by changes in epigenetic marks that are associated with open chromatin states [73]. These findings suggest that MeCP2 establishes chromatin structure during neurodevelopment, and maintains the developmentally established nuclear geometry and chromatin organization in fully developed neurons during adulthood

Summary

Introduction

Methyl CpG binding protein 2 (MeCP2) is a member of a complex family of proteins, the methyl-CpG-binding domain (MBD) protein family, that bind to methylated cytosines. Through the regulation of the neurons’ transcriptional profile, MeCP2 is thought to structural and functional properties of the neurons both during neurodevelopment and in adulthood. We review the less explored role of MeCP2 in the adult brain and argue chromatin maintenance in mature neurons. MeCP2 regulates all stages of neurodevelopment and mice and humans and the presence of neurological deficits in RTT patients from early life suggest adultthat brain function Adulthood, MeCP2 isIna adulthood, critical factor in the maintenance of theinneuronal function It maintains the chromatin and regulates the neuronal transcriptomic profile. It maintains the chromatin structure and regulates the neuronal it appears to maintain a permissive state fortostimulus-dependent gene transcription and regulate transcriptomic profile It appears maintain a permissive state for stimulus-dependent cognitive function. It appears maintain a permissive state for stimulus-dependent cognitive function. and regulate cognitive function

MeCP2 Regulates Neurogenesis and Differentiation

MeCP2 Regulates Synapse and Neuronal Circuit Formation

MeCP2 Is Required for Adult Brain Function

Findings

Conclusions and Outlook