Cited by 154Epigenetics and DNA MethylationGenetics and Neurodevelopmental DisordersAutism Spectrum Disorder Research

Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum

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Zhubi, A, Chen, Y, Dong, E, Cook, E H, Guidotti, A, Grayson, D R·2014·Translational Psychiatry

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms related to altered social interactions/communication and restricted and repetitive behaviors. In addition to genetic risk, epigenetic mechanisms (which include DNA methylation/demethylation) are thought to be important in the etiopathogenesis of ASD. We studied epigenetic mechanisms underlying the transcriptional regulation of candidate genes in cerebella of ASD patients, including the binding of MeCP2 (methyl CpG binding protein-2) to the glutamic acid decarboxylase 67 (GAD1), glutamic acid decarboxylase 65 (GAD2), and Reelin (RELN) promoters and gene bodies. Moreover, we performed methyl DNA immunoprecipitation (MeDIP) and hydroxymethyl DNA immunoprecipitation (hMeDIP) to measure total 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the same regions of these genes. The enrichment of 5-hmC and decrease in 5-mC at the GAD1 or RELN promoters detected by 5-hmC and 5-mC antibodies was confirmed by Tet-assisted bisulfite (TAB) pyrosequencing. The results showed a marked and significant increase in MeCP2 binding to the promoter regions of GAD1 and RELN, but not to the corresponding gene body regions in cerebellar cortex of ASD patients. Moreover, we detected a significant increase in TET1 expression and an enrichment in the level of 5-hmC, but not 5-mC, at the promoters of GAD1 and RELN in ASD when compared with CON. Moreover, there was increased TET1 binding to these promoter regions. These data are consistent with the hypothesis that an increase of 5-hmC (relative to 5-mC) at specific gene domains enhances the binding of MeCP2 to 5-hmC and reduces expression of the corresponding target genes in ASD cerebella.

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  • Both GAD1 and reelin genes are reduced in patients with ASD relative to neurotypical controls and are associated with changes in DNA methylation and hydroxymethylation marks within the promoter region leading to MECP2-dependent repression.

    “Both genes are reduced in patients with ASD relative to neurotypical controls and are associated with changes in DNA methylation and hydroxymethylation marks within the promoter region leading to MECP2-dependent repression [ 158 ].”

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Authors
Zhubi, A., Chen, Y., Dong, E., Cook, E. H., Guidotti, A., & Grayson, D. R.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Grayson, D R
Venue
Translational Psychiatry
Published
2014-01-21
Volume
4
Issue
1
Pages
e349-e349
ISSN
2158-3188 (ISSN-L)
OpenAlex
W1984369088
Cited by
154
References
37
Citations by year
2026: 4 · 2025: 10 · 2024: 13 · 2023: 8 · 2022: 11 · 2021: 8 · 2020: 11 · 2019: 13 · 2018: 7 · 2017: 17 · 2016: 21 · 2015: 13 · 2014: 18
FWCI
9.43
Type
journal article
Language
en
Open access
Locations
  • Translational Psychiatry (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NIH P50, HD055751)
  • National Institute of Mental Health (R24MH068855, R01MH093348)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD055751)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
autism spectrum disorder, MeCP2, 5-hydroxymethylcytosine, 5-methylcytosine, DNA methylation, TET1, GAD1, GAD-2, reelin, promoter binding, cerebellum, epigenetic regulation, transcriptional regulation
MeSH terms
Reelin Protein, Cerebellar Cortex, Child Development Disorders, Pervasive, Cytosine, DNA-Binding Proteins, Glutamate Decarboxylase, Humans, Mixed Function Oxygenases, Nerve Tissue Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, Serine Endopeptidases, Tissue Banks, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Epigenesis, Genetic, 5-Methylcytosine, Methyl-CpG-Binding Protein 2

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