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

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.

SUBMITTER: Dyrvig M

PROVIDER: S-EPMC5240986 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Dyrvig Mads M Qvist Per P Lichota Jacek J Larsen Knud K Nyegaard Mette M Børglum Anders D AD Christensen Jane H JH

PloS one 20170117 1

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 BR ...[more]

PMID: 28095495

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Project description:BackgroundEpidemiological studies of DNA methylation profiles may uncover the molecular mechanisms through which genetic and environmental factors contribute to the risk of multifactorial diseases. There are two types of commonly used DNA bioresources, peripheral blood cells (PBCs) and EBV-transformed lymphoblastoid cell lines (LCLs), which are available for genetic epidemiological studies. Therefore, to extend our knowledge of the difference in DNA methylation status between LCLs and PBCs is important in human population studies that use these DNA sources to elucidate the epigenetic risks for multifactorial diseases. We analyzed the methylation status of the autosomes for 192 and 92 DNA samples that were obtained from PBCs and LCLs, respectively, using a human methylation 450 K array. After excluding SNP-associated methylation sites and low-call sites, 400,240 sites were subjected to analysis using a generalized linear model with cell type, sex, and age as the independent variables.ResultsWe found that the large proportion of sites showed lower methylation levels in LCLs compared with PBCs, which is consistent with previous reports. We also found that significantly different methylation sites tend to be located on the outside of the CpG island and in a region relatively far from the transcription start site. Additionally, we observed that the methylation change of the sites in the low-CpG promoter region was remarkable. Finally, it was shown that the correlation between the chronological age and ageing-associated methylation sites in ELOVL2 and FHL2 in the LCLs was weaker than that in the PBCs.ConclusionsThe methylation levels of highly methylated sites of the low-CpG-density promoters in PBCs decreased in the LCLs, suggesting that the methylation sites located in low-CpG-density promoters could be sensitive to demethylation in LCLs. Despite being generated from a single cell type, LCLs may not always be a proxy for DNA from PBCs in studies of epigenome-wide analysis attempting to elucidate the role of epigenetic change in disease risks.

Dataset Information

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

Publications

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

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