Graduate School of Biomedical Sciences; Brudnick Neuropsychiatric Research Institute; Department of Psychiatry
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
Mental Disorders | Molecular and Cellular Neuroscience | Neuroscience and Neurobiology | Psychiatry
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.
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DOI of Published Version
J Neurosci. 2013 Jul 17;33(29):11839-51. doi: 10.1523/JNEUROSCI.1252-13.2013. Link to article on publisher's site
The Journal of neuroscience : the official journal of the Society for Neuroscience
Bharadwaj 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. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1523/JNEUROSCI.1252-13.2013. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/478