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    Regulation of Higher Order Chromatin at GRIN2B and GAD1 Genetic Loci in Human and Mouse Brain: A Dissertation

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    Authors
    Bharadwaj, Rahul
    Faculty Advisor
    Schahram Akbarian, PhD
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Psychiatry
    Document Type
    Doctoral Dissertation
    Publication Date
    2013-02-14
    Keywords
    Dissertations, UMMS
    Chromatin
    Receptors, N-Methyl-D-Aspartate
    Glutamate Decarboxylase
    Brain
    Transcription Initiation Site
    Regulatory Elements, Transcriptional
    Schizophrenia
    Chromatin
    N-Methyl-D-Aspartate Receptors
    Glutamate Decarboxylase
    Brain
    Transcription Initiation Site
    Transcriptional Regulatory Elements
    Schizophrenia
    Genetics and Genomics
    Neuroscience and Neurobiology
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    Abstract
    Little is known about higher order chromatin structures in the human brain and their function in transcription regulation. We employed chromosome conformation capture (3C) to analyze chromatin architecture within 700 Kb surrounding the transcription start site (TSS) of the NMDA receptor and schizophrenia susceptibility gene, GRIN2B, in human and mouse cerebral cortex. Remarkably, both species showed a higher interaction between the TSS and an intronic sequence, enriched for (KRAB) Krueppel associated Box domain binding sites and selectively targeted by the (H3K9) histone 3 lysine 9 specific methyltransferase ESET/SETDB1. Transgenic mice brain cortical nuclei over-expressing Setdb1 showed increased heterochromatin-protein 1 signal at the interacting regions coupled with decreased Grin2b expression. 3C further revealed three long distant chromatin loop interactions enriched with functional enhancer specific (H3K27Ac) histone 3 lysine 27 acetylation signal in GRIN2B expressing tissue (human cortical nuclei and Human Embryonic Kidney - HEK cells). Doxycycline-induced SETDB1 over-expression decreased 2 out of 3 loop interaction frequencies suggesting a possible SETDB1-mediated transcription repression. We also report a specific looping interaction between a region 50Kb upstream of the (GAD1) Glutamic Acid Decarboxylase – 1 gene TSS and the GAD1 TSS in human brain nuclei. GAD1 catalyzes the rate limiting step in (GABA) gamma amino-butyric acid synthesis and is quintessential for inhibitory signaling in the human brain. Clinical studies in schizophrenia brain samples reveal a decreased looping interaction frequency in correspondence with a decrease in gene expression. Our findings provide evidence for the existence of transcription relevant higher order chromatin structures in human brain.
    DOI
    10.13028/M2Q60Q
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32003
    Notes

    Title on signature page: Regulation of Higher Order Chromatin at GRIN2B and GAD1 Gene Loci in Human and Mouse Brain.

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    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2Q60Q
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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