Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia
Authors
Bharadwaj, RahulJiang, Yan
Mao, Wenjie
Jakovcevski, Mira
Dincer, Aslihan
Krueger, Winfried
Garbett, Krassimira
Whittle, Catheryne
Tushir, Jogender S.
Liu, Jia
Sequeira, Adolfo
Vawter, Marquis P.
Gardner, Paul D.
Casaccia, Patrizia
Rasmussen, Theodore
Bunney, William E. Jr.
Mirnics, Karoly
Futai, Kensuke
Akbarian, Schahram
Student Authors
Wenjie MaoAcademic Program
NeuroscienceUMass Chan Affiliations
Gardner LabDepartment of Psychiatry
Brudnick Neuropsychiatric Research Institute
Graduate School of Biomedical Sciences
Futai Lab
Document Type
Journal ArticlePublication Date
2013-07-17Keywords
AnimalsAntipsychotic 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
Mental Disorders
Molecular and Cellular Neuroscience
Neuroscience and Neurobiology
Psychiatry
Metadata
Show full item recordAbstract
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.Source
J Neurosci. 2013 Jul 17;33(29):11839-51. doi: 10.1523/JNEUROSCI.1252-13.2013. Link to article on publisher's siteDOI
10.1523/JNEUROSCI.1252-13.2013Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30229PubMed ID
23864674Notes
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.
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Link to Article in PubMedRights
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.ae974a485f413a2113503eed53cd6c53
10.1523/JNEUROSCI.1252-13.2013