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Cited by 553Epigenetics and DNA MethylationSchizophrenia research and treatmentGenomics and Chromatin Dynamics

Reelin promoter hypermethylation in schizophrenia

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Grayson, Dennis R., Jia, Xiaomei, Chen, Ying, Sharma, Rajiv P., Mitchell, Colin P., Guidotti, Alessandro, Costa, Erminio·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0503736102PMC PMC1166626
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Abstract

Reelin mRNA and protein levels are reduced by approximately 50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair -527 to base pair +322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions -134 and 139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.

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  • Epigenetic biomarkers could guide novel epigenetic therapies in patients with hypermethylated GAD1 or RELN who may benefit from HDAC inhibitors or DNMT inhibitors to restore expression of key neuroplasticity genes.

    “Additionally, epigenetic biomarkers could be used to guide novel epigenetic therapies in patients with hypermethylated GAD1 or RELN who may benefit from HDAC inhibitors or DNMT inhibitors to restore expression of key neuroplasticity genes (130).”

    From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [130]

    The Abstract reports increased RELN promoter methylation in schizophrenia, and the Discussion proposes DNMT1 and histone deacetylases as potential drug targets. The Discussion also reports that the HDAC inhibitor valproic acid increased reelin expression in cells and reversed its down-regulation in a mouse model. The paper does not establish GAD1 promoter hypermethylation, biomarker-guided patient selection, or benefit from HDAC or DNMT inhibitors in patients. (LLM, conf=0.87)

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Authors
Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., & Costa, E.
Affiliations
University of Illinois Chicago (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-06-16
Volume
102
Issue
26
Pages
9341-9346
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0503736102
PMC
PMC1166626
OpenAlex
W2009680012
Cited by
553
References
37
Citations by year
2026: 8 · 2025: 8 · 2024: 5 · 2023: 9 · 2022: 16 · 2021: 11 · 2020: 16 · 2019: 6 · 2018: 15 · 2017: 19 · 2016: 35 · 2015: 36 · 2014: 52 · 2013: 38 · 2012: 50
FWCI
12.80
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • McGill University
  • Cain Foundation
  • National Institutes of Health
  • National Institute of Mental Health (MH-062188, R01MH062188, MH 62682, R01MH062090, MH062090, R01MH062682)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
reelin, promoter hypermethylation, DNA methylation, schizophrenia, CpG islands, DNMT1, glutamic acid decarboxylase 67, cortical neurons, postmortem brain, cis-regulatory elements, gene expression regulation
MeSH terms
Reelin Protein, Binding, Competitive, Cytosine, DNA, Gene Expression Regulation, Humans, Kinetics, Models, Genetic, Nerve Tissue Proteins, Oligonucleotides, Promoter Regions, Genetic, RNA, Messenger, Schizophrenia, Serine Endopeptidases, Sulfites, Time Factors, Transfection, Cell Adhesion Molecules, Neuronal, Extracellular Matrix Proteins, Sequence Analysis, DNA, Genes, Reporter, CpG Islands, DNA Methylation

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