PMID- 25881116
OWN - NLM
STAT- MEDLINE
DCOM- 20160615
LR  - 20181113
IS  - 1740-634X (Electronic)
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 40
IP  - 11
DP  - 2015 Oct
TI  - Hypermethylation of BDNF and SST Genes in the Orbital Frontal Cortex of Older 
      Individuals: A Putative Mechanism for Declining Gene Expression with Age.
PG  - 2604-13
LID - 10.1038/npp.2015.107 [doi]
AB  - 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.
FAU - McKinney, Brandon C
AU  - McKinney BC
AD  - Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, 
      PA, USA.
FAU - Lin, Chien-Wei
AU  - Lin CW
AD  - Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Oh, Hyunjung
AU  - Oh H
AD  - Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, 
      PA, USA.
AD  - Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Tseng, George C
AU  - Tseng GC
AD  - Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Lewis, David A
AU  - Lewis DA
AD  - Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, 
      PA, USA.
AD  - Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Sibille, Etienne
AU  - Sibille E
AD  - Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, 
      PA, USA.
AD  - Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
AD  - Campbell Family Mental Health Research Institute of CAMH, Departments of 
      Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, ON, 
      Canada.
LA  - eng
GR  - R01 MH093723/MH/NIMH NIH HHS/United States
GR  - R01 MH077159/MH/NIMH NIH HHS/United States
GR  - T32 MH016804/MH/NIMH NIH HHS/United States
GR  - R01MH077159/MH/NIMH NIH HHS/United States
GR  - R01MH093723/MH/NIMH NIH HHS/United States
GR  - K02 MH084060/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150416
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (RNA, Messenger)
RN  - 51110-01-1 (Somatostatin)
RN  - 7171WSG8A2 (BDNF protein, human)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aging/genetics/*metabolism
MH  - Brain/*metabolism
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cohort Studies
MH  - DNA Methylation/*physiology
MH  - Female
MH  - Gene Expression/physiology
MH  - Gene Expression Profiling
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Prefrontal Cortex/growth & development/*metabolism
MH  - RNA, Messenger/metabolism
MH  - Somatostatin/*metabolism
PMC - PMC4569950
EDAT- 2015/04/17 06:00
MHDA- 2016/06/16 06:00
PMCR- 2016/10/01
CRDT- 2015/04/17 06:00
PHST- 2014/12/03 00:00 [received]
PHST- 2015/03/20 00:00 [revised]
PHST- 2015/04/08 00:00 [accepted]
PHST- 2015/04/17 06:00 [entrez]
PHST- 2015/04/17 06:00 [pubmed]
PHST- 2016/06/16 06:00 [medline]
PHST- 2016/10/01 00:00 [pmc-release]
AID - npp2015107 [pii]
AID - 10.1038/npp.2015.107 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2015 Oct;40(11):2604-13. doi: 10.1038/npp.2015.107. Epub 
      2015 Apr 16.