title: 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.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.|Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Dyrvig
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.|Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Qvist
authors.affiliation: Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
authors.forename: Jacek
authors.initials: J
authors.lastname: Lichota
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Knud
authors.initials: K
authors.lastname: Larsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.|Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.|Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.|Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus University, Aarhus, Denmark.|Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
authors.forename: Jane H
authors.identifier: http://orcid.org/0000-0002-0009-2991
authors.initials: JH
authors.lastname: Christensen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D000092468:Bromodomain Containing Proteins
chemical_list: D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D009687:Nuclear Proteins; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins