@article {Rajkumar257170, author = {Anto P. Rajkumar and Per Qvist and Sanne H. Larsen and Ross Lazarus and Jonatan Pallesen and Nicoletta Nava and Gudrun Winther and Nico Liebenberg and Veerle Paternoster and Tue Fryland and Johan Palmfeldt and Kim Fejgin and Arne M{\o}rk and Mette Nyegaard and Bente Pakkenberg and Michael Didriksen and Jens R. Nyengaard and Gregers Wegener and Ole Mors and Jane H. Christensen and Anders D. B{\o}rglum}, title = {The neurobiology of BRD1 implicates sex-biased dysregulation of nuclear receptor signaling in mental disorders}, elocation-id = {257170}, year = {2018}, doi = {10.1101/257170}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2018/04/07/257170}, eprint = {https://www.biorxiv.org/content/early/2018/04/07/257170.full.pdf}, journal = {bioRxiv} }