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.

Identification of DNA motifs that regulate DNA methylation

“…We observed an average 11.7% mQTL discovery rate at the motif sites compared to 2.3% in the background (Figure 3A, upper left panel). This enrichment difference is most prominent around transcription start site, suggesting that the identified motifs have stronger impact on methylation at TSS (Figure 2B) [60][61][62] . Enrichment of mQTL in both MM and UM sites was also found in three additional human methylome datasets using the reported mQTLs in the original studies [63][64][65] (Figure S3A), which confirms the generality of this observation.…”

DNA methylation of membrane‐bound catechol‐O‐methyltransferase in Malaysian schizophrenia patients

“…The interactions between genotype, DNA methylation, and gene expression in schizophrenia have been documented in previous studies. Some of these studies were related to the COMT gene, while others were not . There were nine documented single nucleotide polymorphisms (SNP) within the 109bp of the CpG island’s rich studied region.…”

“…Some of these studies 15,51 were related to the COMT gene, while others were not. 52,53 There were nine documented single nucleotide polymorphisms (SNP) within the 109bp of the CpG island's rich studied region. The minor allele frequency (MAF) of these nine SNP was extremely rare with estimated frequency of <0.1% (Chr22: 19 941 607-19 969 975; www.ensembl.org).…”

Dissecting the Epigenetic Changes Induced by Non-Antipsychotic Mood Stabilizers on Schizophrenia and Affective Disorders: A Systematic Review

“…Twenty-one described studies of rodent samples (Tremolizzo et al, 2002;Dong et al, 2005;Tremolizzo et al, 2005;Kim et al, 2008;Dong et al, 2010;Hobara et al, 2010;Perisic et al, 2010;Matrisciano et al, 2011;Wang et al, 2012;Zimmermann et al, 2012;Calabrese et al, 2013;Leng et al, 2013;Ookubo et al, 2013;Liu et al, 2014;Mackowiak et al, 2014;Balasubramanian et al, 2015;Bator et al, 2015;Dwivedi and Zhang, 2015;Lee et al, 2015;Leng et al, 2016;Bahna and Niles, 2017). Seven articles studied human cell lines (Asai et al, 2013;Kao et al, 2013;Dyrvig et al, 2017;Zong et al, 2017;Billingsley et al, 2018;Dyrvig et al, 2019;Manca et al, 2019) and eight focused on blood samples of subjects diagnosed with either of the selected psychiatric disorders (Gavin et al, 2009;D'Addario et al, 2012;Dell'Osso et al, 2014;Huzayyin et al, 2014;Burghardt et al, 2015;Burghardt et al, 2016;Houtepen et al, 2016;Bengesser et al, 2018). One article studied rodents and human cell lines and subjects (Kaminsky et al, 2015) and one focused on patients and human cell lines (Kakiuchi et al, 2003).…”

“…Study of human neuroblastoma and glioblastoma cells offer a window of what might happen in vivo and might be better models than HeLa adenocarcinoma cells to investigate the effects of mood stabilizers, due to their neuronal characteristics (Dyrvig et al, 2017).…”