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The bromodomain containing 1 gene,  BRD1  is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the  BRD1  locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced  BRD1  expression. Insights into the transcriptional regulation of  BRD1  and the pathogenic mechanisms associated with  BRD1  risk variants, however, remain sparse. By studying transcripts in human HeLa and SH-SY5Y cells we provide evidence for differences in relative expression of  BRD1  transcripts with three alternative 5’ UTRs (exon 1C, 1B, and 1A). We further show that expression of these transcript variants covaries negatively with DNA methylation proportions in their upstream promoter regions suggesting that promoter usage might be regulated by DNA methylation. In line with findings that the risk allele of the rs138880 SNP in the  BRD1  promoter region correlates with reduced  BRD1  expression, we find that it is also associated with moderate regional  BRD1  promoter hypermethylation in both adipose tissue and blood. Importantly, we demonstrate by inspecting available DNA methylation and expression data that these regions undergo changes in methylation during fetal brain development and that differences in their methylation proportions in fetal compared to postnatal frontal cortex correlate significantly with  BRD1  expression. These findings suggest that  BRD1  may be dysregulated in both the developing and mature brain of risk allele carriers. Finally, we demonstrate that commonly used mood stabilizers Lithium, Valproate, and Carbamazepine affect the expression of  BRD1  in SH-SY5Y cells. Altogether this study indicates a link between genetic risk and epigenetic dysregulation of  BRD1  which raises interesting perspectives for targeting the mechanisms pharmacologically.

DNA Methylation Analysis of BRD1 Promoter Regions and the Schizophrenia rs138880 Risk Allele