Evolving role of MeCP2 in Rett syndrome and autism

Abstract

Rett syndrome is an X-linked autism-spectrum disorder caused by mutations in MECP2, encoding methyl CpG-binding protein 2. Since the discovery of MECP2 mutations as the genetic cause of Rett syndrome, the understanding of MeCP2 function has evolved. Although MeCP2 was predicted to be a global transcriptional repressor of methylated promoters, large-scale combined epigenomic approaches of MeCP2 binding, methylation and gene expression have demonstrated that MeCP2 binds preferentially to intergenic and intronic regions, and sparsely methylated promoters of active genes. This review compares the evolution of thought within two ‘classic’ epigenetic mechanisms of parental imprinting and X chromosome inactivation to that of the MeCP2 field, and considers the future relevance of integrated epigenomic databases to understanding autism and Rett syndrome.

Keywords: MeCP2; Rett syndrome; X chromosome inactivation; autism; chromatin; epigenetic; imprinting; methylation.

Figure 1. Evolving models of MeCP2 have come full circle

Models explaining the functional role of MeCP2 in the nucleus have evolved since the transcriptional repressor model of the 1990s. A structural model was later proposed based on studies showing MeCP2 associating with itself and DNA to form dense chromatin structures, consistent with its localization to nuclear heterochromatin. A ‘loop and recruit’ model incorporates a role for MeCP2 in chromatin loop structure, nuclear matrix binding, recruitment of RNA splicing and chromatin remodeling factors. An ‘active gene modulator’ model was supported by integrated epigenomic analyses showing MeCP2 binding to active gene promoters, but primarily to intronic and intergenic sites. And lastly, a transcriptional activator model was proposed based on the interaction of MeCP2 with the transcription factor CREB1. While the evolution of thought on MeCP2 has come full circle, the diversity of models is expected to reflect the diversity of roles for MeCP2 in vivo. The challenge for the field in the future is to determine which of the diverse MeCP2 roles are essential for the postnatal brain that lead to Rett syndrome when deficient. HDAC: Histone deacetylase.

Figure 2. Combined epigenomic profiles at the HOXA gene locus exemplify the concordance of MeCP2 and gene activity with low methylation

Data taken from genome-wide promoter array analyses from Yasui et al. [10] is mapped at the HOXA gene locus on human chromosome 7, for which tissue-specific expression differences correlate with epigenetic markers. HOXA9 is poorly expressed in neurons and has high promoter methylation (MeDIP, blue), low MeCP2 binding (red), and low Pol2 association (green). In contrast, the active HOXA13 promoter shows low methylation but high MeCP2 and Pol2 binding. Overall, there was a striking correlation between MeCP2 and Pol2 chromatin immuno precipitation signals throughout the genome, exemplified at this locus of variable gene activity.