Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters
Kim, Se Young
Baker, Stephen P.
UMass Chan AffiliationsDepartment of Psychiatry
Department of Cell Biology
Information Services, Academic Computing Services
Document TypeJournal Article
Mice, Inbred C57BL
Mice, Mutant Strains
Myeloid-Lymphoid Leukemia Protein
Promoter Regions (Genetics)
Medicine and Health Sciences
Neuroscience and Neurobiology
MetadataShow full item record
AbstractAlterations 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.
SourceJ Neurosci. 2007 Oct 17;27(42):11254-62. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/35289
Co-author Hsien-Sung Huang is a student in the Neuroscience program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.
Related ResourcesLink to article in PubMed