Faculty Collaboration Database

Hypermethylation of BDNF and SST Genes in the Orbital Frontal Cortex of Older Individuals: A Putative Mechanism for Declining Gene Expression with Age. Neuropsychopharmacology 2015 Oct;40(11):2604-13

Date

04/17/2015

Pubmed ID

25881116

Pubmed Central ID

PMC4569950

DOI

10.1038/npp.2015.107

Scopus ID

2-s2.0-84941313544 (requires institutional sign-in at Scopus site)   22 Citations

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.

Author List

McKinney BC, Lin CW, Oh H, Tseng GC, Lewis DA, Sibille E

Author

Chien-Wei Lin PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aging
Brain
Brain-Derived Neurotrophic Factor
Cohort Studies
DNA Methylation
Female
Gene Expression
Gene Expression Profiling
Humans
Male
Middle Aged
Prefrontal Cortex
RNA, Messenger
Somatostatin