Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia

Rahul Bharadwa, Yan Jiang, Wenjie Mao, Mira Jakovcevski, Aslihan Dincer, Winfried Krueger, Krassimira Garbett, Catheryne Whittle, Jogender Singh Tushir, Jia Liu, Adolfo Sequeira, Marquis P. Vawter, Paul D. Gardner, Patrizia Casaccia, Theodore Rasmussen, William E. Bunney, Karoly Mirnics, Kensuke Futai, Schahram Akbarian

Research output: Contribution to journalArticle

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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.Weconclude 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.

Original languageEnglish (US)
Pages (from-to)11839-11851
Number of pages13
JournalJournal of Neuroscience
Volume33
Issue number29
DOIs
StatePublished - Jul 26 2013

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Prefrontal Cortex
gamma-Aminobutyric Acid
Schizophrenia
Chromosomes
Histones
Enzymes
Genome
Gene Expression
GABAergic Neurons
Pluripotent Stem Cells
Intergenic DNA
Neuronal Plasticity
Nucleosomes
Transcription Initiation Site
Gene Expression Regulation
Human Chromosomes
Green Fluorescent Proteins
Reporter Genes
Primates
Transgenic Mice

ASJC Scopus subject areas

  • Neuroscience(all)

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Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia. / Bharadwa, Rahul; Jiang, Yan; Mao, Wenjie; Jakovcevski, Mira; Dincer, Aslihan; Krueger, Winfried; Garbett, Krassimira; Whittle, Catheryne; Tushir, Jogender Singh; Liu, Jia; Sequeira, Adolfo; Vawter, Marquis P.; Gardner, Paul D.; Casaccia, Patrizia; Rasmussen, Theodore; Bunney, William E.; Mirnics, Karoly; Futai, Kensuke; Akbarian, Schahram.

In: Journal of Neuroscience, Vol. 33, No. 29, 26.07.2013, p. 11839-11851.

Research output: Contribution to journalArticle

Bharadwa, R, Jiang, Y, Mao, W, Jakovcevski, M, Dincer, A, Krueger, W, Garbett, K, Whittle, C, Tushir, JS, Liu, J, Sequeira, A, Vawter, MP, Gardner, PD, Casaccia, P, Rasmussen, T, Bunney, WE, Mirnics, K, Futai, K & Akbarian, S 2013, 'Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia', Journal of Neuroscience, vol. 33, no. 29, pp. 11839-11851. https://doi.org/10.1523/JNEUROSCI.1252-13.2013
Bharadwa, Rahul ; Jiang, Yan ; Mao, Wenjie ; Jakovcevski, Mira ; Dincer, Aslihan ; Krueger, Winfried ; Garbett, Krassimira ; Whittle, Catheryne ; Tushir, Jogender Singh ; Liu, Jia ; Sequeira, Adolfo ; Vawter, Marquis P. ; Gardner, Paul D. ; Casaccia, Patrizia ; Rasmussen, Theodore ; Bunney, William E. ; Mirnics, Karoly ; Futai, Kensuke ; Akbarian, Schahram. / Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 29. pp. 11839-11851.
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AU - Jakovcevski, Mira

AU - Dincer, Aslihan

AU - Krueger, Winfried

AU - Garbett, Krassimira

AU - Whittle, Catheryne

AU - Tushir, Jogender Singh

AU - Liu, Jia

AU - Sequeira, Adolfo

AU - Vawter, Marquis P.

AU - Gardner, Paul D.

AU - Casaccia, Patrizia

AU - Rasmussen, Theodore

AU - Bunney, William E.

AU - Mirnics, Karoly

AU - Futai, Kensuke

AU - Akbarian, Schahram

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