The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice

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The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice. / Qvist, Per; Christensen, Jane Hvarregaard; Vardya, Irina; Rajkumar, Anto Praveen; Mørk, Arne; Paternoster, Veerle; Füchtbauer, Ernst-Martin; Pallesen, Jonatan; Fryland, Tue; Dyrvig, Mads; Hauberg, Mads Engel; Lundsberg, Birgitte; Fejgin, Kim; Nyegaard, Mette; Jensen, Kimmo; Nyengaard, Jens Randel; Mors, Ole; Didriksen, Michael; Børglum, Anders Dupont.

I: Biological Psychiatry, Bind 82, Nr. 1, 2017, s. 62-76.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{83e1ffea1dc8460f9f24127c44676264,
title = "The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice",
abstract = "BACKGROUND: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative.METHODS: This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1(+/-) mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters.RESULTS: Brd1(+/-) mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1(+/-) and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D2 [Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]).CONCLUSIONS: Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.",
author = "Per Qvist and Christensen, {Jane Hvarregaard} and Irina Vardya and Rajkumar, {Anto Praveen} and Arne M{\o}rk and Veerle Paternoster and Ernst-Martin F{\"u}chtbauer and Jonatan Pallesen and Tue Fryland and Mads Dyrvig and Hauberg, {Mads Engel} and Birgitte Lundsberg and Kim Fejgin and Mette Nyegaard and Kimmo Jensen and Nyengaard, {Jens Randel} and Ole Mors and Michael Didriksen and B{\o}rglum, {Anders Dupont}",
note = "Copyright {\textcopyright} 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.",
year = "2017",
doi = "10.1016/j.biopsych.2016.08.037",
language = "English",
volume = "82",
pages = "62--76",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier",
number = "1",

}

RIS

TY - JOUR

T1 - The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice

AU - Qvist, Per

AU - Christensen, Jane Hvarregaard

AU - Vardya, Irina

AU - Rajkumar, Anto Praveen

AU - Mørk, Arne

AU - Paternoster, Veerle

AU - Füchtbauer, Ernst-Martin

AU - Pallesen, Jonatan

AU - Fryland, Tue

AU - Dyrvig, Mads

AU - Hauberg, Mads Engel

AU - Lundsberg, Birgitte

AU - Fejgin, Kim

AU - Nyegaard, Mette

AU - Jensen, Kimmo

AU - Nyengaard, Jens Randel

AU - Mors, Ole

AU - Didriksen, Michael

AU - Børglum, Anders Dupont

N1 - Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PY - 2017

Y1 - 2017

N2 - BACKGROUND: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative.METHODS: This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1(+/-) mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters.RESULTS: Brd1(+/-) mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1(+/-) and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D2 [Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]).CONCLUSIONS: Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.

AB - BACKGROUND: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative.METHODS: This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1(+/-) mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters.RESULTS: Brd1(+/-) mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1(+/-) and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D2 [Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]).CONCLUSIONS: Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic, chromatin interactomic, and brain transcriptomic.

U2 - 10.1016/j.biopsych.2016.08.037

DO - 10.1016/j.biopsych.2016.08.037

M3 - Journal article

C2 - 27837920

VL - 82

SP - 62

EP - 76

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

IS - 1

ER -