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

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.

Figure 1

The diverse functions of MeCP2 in gene regulation and chromatin organization.

Figure 2

MECP2 gene and protein isoforms. Schematic illustration of the gene structure of MECP2 and the different domains of the two protein isoforms, MeCP2E1 and MeCP2E2. The primary amino acid composition of the N-terminus of MeCP2E1 and MeCP2E2 is depicted.