title: Conserved chromosome 2q31 conformations are associated with transcriptional regulation of GAD1 GABA synthesis enzyme and altered in prefrontal cortex of subjects with schizophrenia.
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.
authors.affiliation: Graduate School of Biomedical Sciences and Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bharadwaj
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Mao
authors.forename: Mira
authors.initials: M
authors.lastname: Jakovcevski
authors.forename: Aslihan
authors.initials: A
authors.lastname: Dincer
authors.forename: Winfried
authors.initials: W
authors.lastname: Krueger
authors.forename: Krassimira
authors.initials: K
authors.lastname: Garbett
authors.forename: Catheryne
authors.initials: C
authors.lastname: Whittle
authors.forename: Jogender Singh
authors.initials: JS
authors.lastname: Tushir
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Adolfo
authors.initials: A
authors.lastname: Sequeira
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gardner
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia
authors.forename: Theodore
authors.initials: T
authors.lastname: Rasmussen
authors.forename: William E
authors.initials: WE
authors.lastname: Bunney
authors.forename: Karoly
authors.initials: K
authors.lastname: Mirnics
authors.forename: Kensuke
authors.initials: K
authors.lastname: Futai
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002889:Chromosomes, Human, Pair 2; D003024:Clozapine / Q000494:pharmacology; D019175:DNA Methylation; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000235:genetics* / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D006657:Histones; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D003024:Clozapine; D006220:Haloperidol