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dc.contributor.authorHuang, Hsien-Sung
dc.contributor.authorMatevossian, Anouch
dc.contributor.authorWhittle, Catheryne
dc.contributor.authorKim, Se Young
dc.contributor.authorSchumacher, Armin
dc.contributor.authorBaker, Stephen P.
dc.contributor.authorAkbarian, Schahram
dc.date2022-08-11T08:09:11.000
dc.date.accessioned2022-08-23T16:20:28Z
dc.date.available2022-08-23T16:20:28Z
dc.date.issued2007-10-19
dc.date.submitted2008-05-05
dc.identifier.citationJ Neurosci. 2007 Oct 17;27(42):11254-62. <a href="http://dx.doi.org/10.1523/JNEUROSCI.3272-07.2007">Link to article on publisher's site</a>
dc.identifier.issn1529-2401 (Electronic)
dc.identifier.doi10.1523/JNEUROSCI.3272-07.2007
dc.identifier.pmid17942719
dc.identifier.urihttp://hdl.handle.net/20.500.14038/35289
dc.description<p>Co-author Hsien-Sung Huang is a student in the Neuroscience program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.</p>
dc.description.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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17942719&dopt=Abstract ">Link to article in PubMed</a>
dc.subjectAdult
dc.subjectAnimals
dc.subjectCells, Cultured
dc.subjectChild
dc.subject*DNA Methylation
dc.subjectFemale
dc.subjectGlutamate Decarboxylase
dc.subjectHistones
dc.subjectHumans
dc.subjectMale
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Mutant Strains
dc.subjectMyeloid-Lymphoid Leukemia Protein
dc.subjectPrefrontal Cortex
dc.subjectPromoter Regions (Genetics)
dc.subjectRats
dc.subjectSchizophrenia
dc.subjectgamma-Aminobutyric Acid
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.subjectNeuroscience and Neurobiology
dc.subjectPsychiatry
dc.titlePrefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters
dc.typeJournal Article
dc.source.journaltitleThe Journal of neuroscience : the official journal of the Society for Neuroscience
dc.source.volume27
dc.source.issue42
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1033&amp;context=infoservices&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/infoservices/34
dc.identifier.contextkey503915
refterms.dateFOA2022-08-23T16:20:28Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathinfoservices/34
dc.contributor.departmentDepartment of Psychiatry
dc.contributor.departmentDepartment of Cell Biology
dc.contributor.departmentInformation Services, Academic Computing Services
dc.source.pages11254-62


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