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Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters
Open accessAbstract
Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters ( GAD2 , NPY , SST ) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5′ end of GAD1 . Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 ( Mll1 ), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D 2 and D 3 receptors, suggesting that blockade of D 2 -like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.
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“Given the role of this process in establishing active promoters38, it appears likely that the dysregulation of histone methylation may have downstream effects with the potential to disrupt neurodevelopment and coordinated gene expression, as animal studies have demonstrated39.”
From Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways (2015) · cites this paper as [39]
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Metadata
- Authors
- Huang, H.-S., Matevossian, A., Whittle, C., Kim, S. Y., Schumacher, A., Baker, S. P., & Akbarian, S.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Baylor College of Medicine (US)
- Corresponding author
- Akbarian, Schahram
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-10-17
- Volume
- 27
- Issue
- 42
- Pages
- 11254-11262
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6673022
- OpenAlex
- W2124607109
- Cited by
- 352
- References
- 44
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 13 · 2023: 14 · 2022: 19 · 2021: 15 · 2020: 13 · 2019: 12 · 2018: 15 · 2017: 10 · 2016: 27 · 2015: 24 · 2014: 31 · 2013: 27 · 2012: 25
- FWCI
- 14.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institute of Mental Health
- National Institute of Child Health and Human Development
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- schizophrenia, prefrontal cortex, MLL1, histone H3 lysine 4 methylation, GABAergic neurons, GAD1, promoter, chromatin remodeling, clozapine, dopamine D2/D3 receptors, sex differences, brain development
- MeSH terms
- Adult, Animals, Cells, Cultured, Child, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Histones, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Schizophrenia, Prefrontal Cortex, DNA Methylation, Mice, Rats, Myeloid-Lymphoid Leukemia Protein
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