University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Graduate School of Biomedical Sciences; Brudnick Neuropsychiatric Research Institute; Department of Psychiatry

Date

7-17-2013

Document Type

Article

Medical Subject Headings

Animals; Antipsychotic Agents; Cells, Cultured; Chromosomes, Human, Pair 2; Clozapine; DNA Methylation; Down-Regulation; Fibroblasts; Gene Expression Regulation; Glutamate Decarboxylase; Haloperidol; Hippocampus; Histones; Humans; Mice; Mice, Transgenic; Neurons; Prefrontal Cortex; Schizophrenia

Disciplines

Mental Disorders | Molecular and Cellular Neuroscience | Neuroscience and Neurobiology | Psychiatry

Abstract

Little is known about chromosomal loopings involving proximal promoter and distal enhancer elements regulating GABAergic gene expression, including changes in schizophrenia and other psychiatric conditions linked to altered inhibition. Here, we map in human chromosome 2q31 the 3D configuration of 200 kb of linear sequence encompassing the GAD1 GABA synthesis enzyme gene locus, and we describe a loop formation involving the GAD1 transcription start site and intergenic noncoding DNA elements facilitating reporter gene expression. The GAD1-TSS(-50kbLoop) was enriched with nucleosomes epigenetically decorated with the transcriptional mark, histone H3 trimethylated at lysine 4, and was weak or absent in skin fibroblasts and pluripotent stem cells compared with neuronal cultures differentiated from them. In the prefrontal cortex of subjects with schizophrenia, GAD1-TSS(-50kbLoop) was decreased compared with controls, in conjunction with downregulated GAD1 expression. We generated transgenic mice expressing Gad2 promoter-driven green fluorescent protein-conjugated histone H2B and confirmed that Gad1-TSS(-55kbLoop), the murine homolog to GAD1-TSS(-50kbLoop), is a chromosomal conformation specific for GABAergic neurons. In primary neuronal culture, Gad1-TSS(-55kbLoop) and Gad1 expression became upregulated when neuronal activity was increased. We conclude that 3D genome architectures, including chromosomal loopings for promoter-enhancer interactions involved in the regulation of GABAergic gene expression, are conserved between the rodent and primate brain, and subject to developmental and activity-dependent regulation, and disordered in some cases with schizophrenia. More broadly, the findings presented here draw a connection between noncoding DNA, spatial genome architecture, and neuronal plasticity in development and disease.

Rights and Permissions

Citation: J Neurosci. 2013 Jul 17;33(29):11839-51. doi: 10.1523/JNEUROSCI.1252-13.2013. Link to article on publisher's site

Comments

Copyright © 2013 the authors

Publisher PDF posted as allowed by the publisher's author rights policy at http://www.jneurosci.org/site/misc/ifa_policies.xhtml#copyright.

First author Rahul Bharadwaj is a doctoral student in the Interdisciplinary Graduate Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to Article in PubMed

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