Abstract
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.
Highlights
BRD1 encodes the bromodomain-containing protein 1 (BRD1), which is widely expressed in human tissues including the brain [1]
BRD1 exists in a short and long transcript variant resulting from alternative splicing of exon 7 and it has been suggested that transcription from exon 1A results in the long variant whereas transcription from exon 1C results in the short variant [1]
We present evidence that BRD1 transcription is initiated from three alternative promoters that show large differences in activity and might be regulated by DNA methylation
Summary
BRD1 encodes the bromodomain-containing protein 1 (BRD1), which is widely expressed in human tissues including the brain [1]. The BRD1 promoter SNP, rs138880, was recently identified as the variant showing the most significant association with schizophrenia in a large GWAS meta-analysis (>11,000 cases and >10,000 controls) ensued by a family-based replication study (>6,000 individuals including >3,000 cases) [7]. This augmented previous studies linking rs138880 with both schizophrenia and bipolar disorders in large Caucasian case-control samples [8,9] as well as the identification of a susceptibility locus containing BRD1 in the Faroese population [10].
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