title: Hypermethylation of BDNF and SST Genes in the Orbital Frontal Cortex of Older Individuals: A Putative Mechanism for Declining Gene Expression with Age.
abstract: Expression of brain-derived neurotrophic factor (BDNF) and somatostatin (SST) mRNAs in the brain decreases progressively and robustly with age, and lower BDNF and SST expression in the brain has been observed in many brain disorders. BDNF is known to regulate SST expression; however, the mechanisms underlying decreased expression of both genes are not understood. DNA methylation (DNAm) is an attractive candidate mechanism. To investigate the contribution of DNAm to the age-related decline in BDNF and SST expression, the Illumina Infinium HumanMethylation450 Beadchip Array was used to quantify DNAm of BDNF (26 CpG loci) and SST (9 CpG loci) in the orbital frontal cortices of postmortem brains from 22 younger (age <42 years) and 22 older individuals (age >60 years) with known age-dependent BDNF and SST expression differences. Relative to the younger individuals, 10 of the 26 CpG loci in BDNF and 8 of the 9 CpG loci in SST were significantly hypermethylated in the older individuals. DNAm in BDNF exons/promoters I, II, and IV negatively correlated with BDNF expression (r=-0.37, p<0.05; r=-0.40, p<0.05; r=-0.24, p=0.07), and DNAm in SST 5' UTR and first exon/intron negatively correlated with SST expression (r=-0.48, p<0.01; r=-0.63, p<0.001), respectively. An expanded set of BDNF- and GABA-related genes exhibited similar age-related changes in DNAm and correlation with gene expression. These results suggest that DNAm may be a proximal mechanism for decreased expression of BDNF, SST, and other BDNF- and GABA-related genes with brain aging and, by extension, for brain disorders in which their expression is decreased.
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
authors.forename: Brandon C
authors.initials: BC
authors.lastname: McKinney
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Chien-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.|Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.|Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.|Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.|Campbell Family Mental Health Research Institute of CAMH, Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Etienne
authors.initials: E
authors.lastname: Sibille
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D015331:Cohort Studies; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000254:growth & development / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D013004:Somatostatin; C579455:BDNF protein, human