title: Functional DNA methylation in a transcript specific 3'UTR region of TrkB associates with suicide.
abstract: Previous studies indicate that a subgroup of suicide completers has low cortical brain expression levels of TrkB-T1, a TrkB gene transcript that is highly expressed in astrocytes. Epigenetic modifications, including methylation changes in the TrkB promoter, partially explain TrkB-T1 low expression levels in brain tissue from suicide completers. The aim of this study was to investigate whether methylation changes in other regions of the TrkB gene could also contribute to the significant downregulation of the TrkB-T1 transcript observed in the brain of suicide completers. Methylation levels were assessed on BA8/9 from suicide completers expressing low TrkB-T1 transcript levels and controls, using custom-made Agilent arrays tiling the whole TrkB gene. After statistical correction for multiple testing, five probes located in the TrkB-T1 3'UTR region were found hypermethylated in the frontal cortex of suicide completers. These results were validated for four CpGs spanning a 150 bp sequence by cloning and Sanger sequencing bisulfite treated DNA. We found a significant correlation between the methylation level at these four CpGs and TrkB-T1 expression in BA8/9. Site-specific hypermethylation on this 3'UTR sequence induced decreased luciferase activity in reporter gene cell assays. Site-specific differential methylation in the TrkB-T1 3'UTR region associates with functional changes in TrkB-T1 expression and may play a significant role in the important decrease of cortical TrkB-T1 expression observed among suicide completers.
authors.affiliation: McGill Group for Suicide Studies; Douglas Hospital Research Institute; McGill University; Montreal, QC Canada.
authors.forename: Gilles
authors.initials: G
authors.lastname: Maussion
authors.affiliation: McGill Group for Suicide Studies; Douglas Hospital Research Institute; McGill University; Montreal, QC Canada.
authors.forename: Jennie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Departments of Pharmacology and Therapeutics; McGill University; Montreal, QC Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Suderman
authors.affiliation: McGill Group for Suicide Studies; Douglas Hospital Research Institute; McGill University; Montreal, QC Canada.
authors.forename: Alpha
authors.initials: A
authors.lastname: Diallo
authors.affiliation: McGill Group for Suicide Studies; Douglas Hospital Research Institute; McGill University; Montreal, QC Canada.
authors.forename: Corina
authors.initials: C
authors.lastname: Nagy
authors.affiliation: McGill Group for Suicide Studies; Douglas Hospital Research Institute; McGill University; Montreal, QC Canada.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Arnovitz
authors.affiliation: McGill Group for Suicide Studies; Douglas Hospital Research Institute; McGill University; Montreal, QC Canada.
authors.forename: Naguib
authors.initials: N
authors.lastname: Mechawar
authors.affiliation: McGill Group for Suicide Studies; Douglas Hospital Research Institute; McGill University; Montreal, QC Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020813:Receptor, trkB; D013405:Suicide; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: BA8/9; DNA methylation; TrkB-T1; astrocytes; epigenetics; luciferase assay; suicide