title: 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.
authors.affiliation: Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, Davis, CA 95616, USA.
authors.forename: Raman P
authors.initials: RP
authors.lastname: Nagarajan
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Patzel
authors.forename: Michelle
authors.initials: M
authors.lastname: Martin
authors.forename: Dag H
authors.initials: DH
authors.lastname: Yasui
authors.forename: Susan E
authors.initials: SE
authors.lastname: Swanberg
authors.forename: Irva
authors.initials: I
authors.lastname: Hertz-Picciotto
authors.forename: Robin L
authors.initials: RL
authors.lastname: Hansen
authors.forename: Judy
authors.initials: J
authors.lastname: Van de Water
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.forename: Ruby
authors.initials: R
authors.lastname: Jiang
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
mesh_terms: D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008745:Methylation; D011110:Polymorphism, Genetic / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: D017931:DNA Primers; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2