Linking epigenetics to human disease and Rett syndrome: the emerging novel and challenging concepts in MeCP2 research.

Robby Mathew Zachariah,Mojgan Rastegar

doi:10.1155/2012/415825

Abstract

Epigenetics refer to inheritable changes beyond DNA sequence that control cell identity and morphology. Epigenetics play key roles in development and cell fate commitments and highly impact the etiology of many human diseases. A well-known link between epigenetics and human disease is the X-linked MECP2 gene, mutations in which lead to the neurological disorder, Rett Syndrome. Despite the fact that MeCP2 was discovered about 20 years ago, our current knowledge about its molecular function is not comprehensive. While MeCP2 was originally found to bind methylated DNA and interact with repressor complexes to inhibit and silence its genomic targets, recent studies have challenged this idea. Indeed, depending on its interacting protein partners and target genes, MeCP2 can act either as an activator or as a repressor. Furthermore, it is becoming evident that although Rett Syndrome is a progressive and postnatal neurological disorder, the consequences of MeCP2 deficiencies initiate much earlier and before birth. To comprehend the novel and challenging concepts in MeCP2 research and to design effective therapeutic strategies for Rett Syndrome, a targeted collaborative effort from scientists in multiple research areas to clinicians is required.

Highlights

The term epigenetics refers to inheritable changes in gene expression that control cellular phenotype and fate decisions without alterations in the underlying DNA sequence [1]
The methylation of DNA molecules is processed by a group of enzymes called DNA methyltransferases (DNMTs)
The mammalian DNMT family consists of 5 proteins (DNMT1, 2, 3A, 3B, 3L)

Summary

Introduction

The term epigenetics refers to inheritable changes in gene expression that control cellular phenotype and fate decisions without alterations in the underlying DNA sequence [1]. Histone modifications are dynamic and include acetylation, methylation, isomerization, phosphorylation, sumoylation, and ubiquitination [1, 2] The combination of such modifications confers enormous flexibility in terms of functional response of an individual cell towards extracellular signals and environmental stimuli. Further investigations on MeCP2 function led to the discovery of its role as a transcriptional repressor and association with corepressor complexes such as mSin3A and HDACs [21, 22] This was not surprising, since DNA methylation itself was considered to be a repressive mark. We will discuss the role of MeCP2 in chromatin structure and nuclear architecture of neurons, its competition with the linker histone H1, the MECP2 transcript products and diverse functional domains of MeCP2 protein, as well as MeCP2 expression and genomic targets in neurons and glia

The MECP2 Gene Structure and Its Splice Variants

The Expression Pattern of MeCP2

MeCP2 Genomic Distributions and Target Genes

Human Diseases Associated with MECP2 Mutations

Findings

Closing Remarks