MECP2 promoter methylation and X chromosome inactivation in autism

Abstract

Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were peformed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCTC-binding factor (CTCF) bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes.

Sensitive Periods in Epigenetics: Bringing us Closer to Complex Behavioral Phenotypes

“…This suggests behavior can be mediated epigenetically by external factors however some predisposing factor is required to engage the epigenetic machinery required for change. Human blood has also been used to assess DNA methylation changes in other mental disorders such as posttraumatic stress disorder [58], bipolar disorder [59][60] and autism [61].…”

DNA methylation in early development

“…This disorder almost exclusively affects females because the complete loss of the X-linked MeCP2 gene in males is believed to be lethal. DNA methylation of the MeCP2 promoter has also been found in patients with autism spectrum disorder (Nagarajan et al, 2006(Nagarajan et al, , 2008. Thus, loss of this methyl DNA binding protein can also be due to aberrant DNA methylation of its regulatory elements.…”

Relationship between Methyl CpG Binding Protein 2 and JC Viral Proteins

“…The second hypothesis is the epigenetic regulation of MeCP2 expression. MeCP2 promoter methylation and decreased MeCP2 expression have been reported in the study of autistic male brains (47,48). The differences in epigenetic factors between PML brains and our system in vitro may explain the discrepancy, and genomic demethylation or acetylation may play an important role.…”