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MECP2 promoter methylation and X chromosome inactivation in autism

Authors

  • Raman P. Nagarajan,

    1. Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, Davis, California
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  • Katherine A. Patzel,

    1. Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, Davis, California
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  • Michelle Martin,

    1. Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, Davis, California
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  • Dag H. Yasui,

    1. Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, Davis, California
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  • Susan E. Swanberg,

    1. Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, Davis, California
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  • Irva Hertz-Picciotto,

    1. Department of Public Health Sciences and Division of Epidemiology, Divisions of Epidemiology and Environmental and Occupational Health, University of California, Davis, California
    2. Medical Institute for Neurodevelopmental Disorders, University of California, Davis, California
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  • Robin L. Hansen,

    1. Medical Institute for Neurodevelopmental Disorders, University of California, Davis, California
    2. Department of Pediatrics, University of California, Davis, California
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  • Judy Van de Water,

    1. Medical Institute for Neurodevelopmental Disorders, University of California, Davis, California
    2. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, California
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  • Isaac N. Pessah,

    1. Medical Institute for Neurodevelopmental Disorders, University of California, Davis, California
    2. Department of Veterinary Molecular Biosciences, University of California, Davis, California
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  • Ruby Jiang,

    1. Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Wendy P. Robinson,

    1. Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Janine M. LaSalle

    Corresponding author
    1. Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, Davis, California
    • Medical Microbiology and Immunology and Rowe Program in Human Genetics, University of California, One Shields Avenue, Davis, CA 95616
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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 performed 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 CCCTC-binding factor (CTCF) is 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.

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