RT Journal Article
SR Electronic
T1 The neurobiology of BRD1 implicates sex-biased dysregulation of nuclear receptor signaling in mental disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 257170
DO 10.1101/257170
A1 Anto P. Rajkumar
A1 Per Qvist
A1 Sanne H. Larsen
A1 Ross Lazarus
A1 Jonatan Pallesen
A1 Nicoletta Nava
A1 Gudrun Winther
A1 Nico Liebenberg
A1 Veerle Paternoster
A1 Tue Fryland
A1 Johan Palmfeldt
A1 Kim Fejgin
A1 Arne Mørk
A1 Mette Nyegaard
A1 Bente Pakkenberg
A1 Michael Didriksen
A1 Jens R. Nyengaard
A1 Gregers Wegener
A1 Ole Mors
A1 Jane H. Christensen
A1 Anders D. Børglum
YR 2018
UL http://biorxiv.org/content/early/2018/04/07/257170.abstract
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.