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

Date Published: January 17, 2017

Publisher: Public Library of Science

Author(s): Mads Dyrvig, Per Qvist, Jacek Lichota, Knud Larsen, Mette Nyegaard, Anders D. Børglum, Jane H. Christensen, Lorenzo Chiariotti.

http://doi.org/10.1371/journal.pone.0170121

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.

Partial Text

BRD1 encodes the bromodomain-containing protein 1 (BRD1), which is widely expressed in human tissues including the brain [1]. BRD1 has been identified in protein complexes possessing acetyltransferase activity towards histone H3 [2,3] and it binds chromatin in regions adjacent to transcription start sites (TSSs) of numerous genes [3,4]. Inactivation of Brd1 in mice is incompatible with postnatal life due to severe embryonic mal-development including impaired neural tube closure [3]. Cerebral changes in Brd1 expression upon electroconvulsive seizures [5] and chronic restraint stress in rats [6], suggest an important function of BRD1 in the mature CNS that might include a role in gene regulatory processes underlying adaptation to stress.

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. We also find that the schizophrenia-associated C allele of rs138880 not only correlates with slightly reduced BRD1 expression but also with moderately increased DNA methylation in BRD1 promoter regions in both adipose tissue and blood. Interestingly, we find that these risk allele hypermethylated regions undergo changes in methylation during brain development and that these changes correlate well with changes in BRD1 expression. Finally, we demonstrate that commonly used mood stabilizers affect the expression of BRD1 in SH-SY5Y cells, however most likely by mechanisms other than DNA methylation changes in the promoter regions studied.

 

Source:

http://doi.org/10.1371/journal.pone.0170121

 

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