Document Detail

Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters.
MedLine Citation:
PMID:  17942719     Owner:  NLM     Status:  MEDLINE    
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 D2 and D3 receptors, suggesting that blockade of D2-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.
Hsien-Sung Huang; Anouch Matevossian; Catheryne Whittle; Se Young Kim; Armin Schumacher; Stephen P Baker; Schahram Akbarian
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  27     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2007 Oct 
Date Detail:
Created Date:  2007-10-18     Completed Date:  2007-11-08     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11254-62     Citation Subset:  IM    
Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
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MeSH Terms
Cells, Cultured
DNA Methylation*
Glutamate Decarboxylase / biosynthesis,  genetics
Histones / genetics,  metabolism*
Mice, Inbred C57BL
Mice, Mutant Strains
Myeloid-Lymphoid Leukemia Protein / genetics,  physiology*
Prefrontal Cortex / enzymology,  metabolism*,  pathology
Promoter Regions, Genetic / physiology*
Schizophrenia / enzymology,  genetics,  metabolism*
gamma-Aminobutyric Acid / genetics,  physiology*
Reg. No./Substance:
0/Histones; 0/MLL protein, human; 149025-06-9/Myeloid-Lymphoid Leukemia Protein; 56-12-2/gamma-Aminobutyric Acid; EC Decarboxylase; EC decarboxylase 1

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