PT  - JOURNAL ARTICLE
AU  - Anto P. Rajkumar
AU  - Per Qvist
AU  - Sanne H. Larsen
AU  - Ross Lazarus
AU  - Jonatan Pallesen
AU  - Nicoletta Nava
AU  - Gudrun Winther
AU  - Nico Liebenberg
AU  - Veerle Paternoster
AU  - Tue Fryland
AU  - Johan Palmfeldt
AU  - Kim Fejgin
AU  - Arne Mørk
AU  - Mette Nyegaard
AU  - Bente Pakkenberg
AU  - Michael Didriksen
AU  - Jens R. Nyengaard
AU  - Gregers Wegener
AU  - Ole Mors
AU  - Jane H. Christensen
AU  - Anders D. Børglum
TI  - The neurobiology of BRD1 implicates sex-biased dysregulation of nuclear receptor signaling in mental disorders
AID  - 10.1101/257170
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 257170
4099  - http://biorxiv.org/content/early/2018/04/07/257170.short
4100  - http://biorxiv.org/content/early/2018/04/07/257170.full
AB  - The schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/− mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/− mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/− mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/− mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.