MECP2 promoter methylation and x chromosome inactivation in autism

Raman P. Nagarajan, Katherine A. Patzel, Michelle Martin, Dag H. Yasui, Susan E. Swanberg, Irva Hertz-Picciotto, Robin L Hansen, Judith A Van de Water, Isaac N Pessah, Ruby Jiang, Wendy P. Robinson, Janine M LaSalle

Research output: Contribution to journalArticle

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Abstract

Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by thediscovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism malebrain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylationpatterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were performed on brain andblood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brainDNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated inmales and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCCTC-bindingfactor (CTCF) is bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylationtransition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting apossible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. Inaddition, autistic female brain DNA samples showed eviDence for aberrant MECP2 promoter methylation as an increase inthe number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To furtherinvestigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers ofmales with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observedcompared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due tolocus-specific rather than global X chromosome methylation changes.

Original languageEnglish (US)
Pages (from-to)169-178
Number of pages10
JournalAutism Research
Volume1
Issue number3
DOIs
StatePublished - 2008

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Keywords

  • Epigenetics
  • MECP2
  • Postmortem brain
  • X chromosome inactivation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Genetics(clinical)
  • Medicine(all)

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