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Inactivation of the Schizophrenia-associated BRD1 gene in Brain Causes Failure-to-thrive, Seizure Susceptibility and Abnormal Histone H3 Acetylation and N-tail Clipping

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  • Veerle Paternoster, iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Lundbeck Fdn Initiat Integrat Psychiat Res, Centre for Integrative Sequencing, iSEQ, Aarhus University, Centre for Genomics and Personalized Medicine
  • ,
  • Anders Valdemar Edhager
  • ,
  • Per Qvist, iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Lundbeck Fdn Initiat Integrat Psychiat Res, Centre for Integrative Sequencing, iSEQ, Aarhus University, Centre for Genomics and Personalized Medicine
  • ,
  • Julie Grinderslev Donskov
  • Pavel Shliaha, University of Southern Denmark
  • ,
  • Ole Nørregaard Jensen, University of Southern Denmark
  • ,
  • Ole Mors
  • Anders Lade Nielsen
  • Anders Dupont Børglum
  • Johan Palmfeldt
  • Jane Hvarregaard Christensen

Genetic studies have repeatedly shown that the Bromodomain containing 1 gene, BRD1, is involved in determining mental health, and the importance of the BRD1 protein for normal brain function has been studied in both cell models and constitutive haploinsufficient Brd1+/- mice. Homozygosity for inactivated Brd1 alleles is lethal during embryonic development in mice. In order to further characterize the molecular functions of BRD1 in the brain, we have developed a novel Brd1 knockout mouse model (Brd1-/-) with bi-allelic conditional inactivation of Brd1 in the central nervous system. Brd1-/- mice were viable but smaller and with reduced muscle strength. They showed reduced exploratory behavior and increased sensitivity to pentylenetetrazole-induced seizures supporting the previously described GABAergic dysfunction in constitutive Brd1+/- mice. Because BRD1 takes part in protein complexes with histone binding and modifying functions, we investigated the effect of BRD1 depletion on the global histone modification pattern in mouse brain by mass spectrometry. We found decreased levels of histone H3 acetylation (H3K9ac, H3K14ac, and H3K18ac) and increased N-tail clipping in consequence of BRD1 depletion. Collectively, the presented results support that BRD1 controls gene expression at the epigenetic level by regulating histone H3 proteoforms in the brain.

Original languageEnglish
JournalMolecular Neurobiology
Volume58
Issue9
Pages (from-to)4495-4505
Number of pages11
ISSN0893-7648
DOIs
Publication statusPublished - Sep 2021

    Research areas

  • BRD1, Central nervous system, Histone, Mass spectrometry, Pentylenetetrazole, Post-translational modifications

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