title: Hepatic DNA hydroxymethylation is site-specifically altered by chronic alcohol consumption and aging.
abstract: OBJECTIVE
  Global DNA hydroxymethylation is markedly decreased in human cancers, including hepatocellular carcinoma, which is associated with chronic alcohol consumption and aging. Because gene-specific changes in hydroxymethylcytosine may affect gene transcription, giving rise to a carcinogenic environment, we determined genome-wide site-specific changes in hepatic hydroxymethylcytosine that are associated with chronic alcohol consumption and aging.
  
  
  METHODS
  Young (4 months) and old (18 months) male C57Bl/6 mice were fed either an ethanol-containing Lieber-DeCarli liquid diet or an isocaloric control diet for 5 weeks. Genomic and gene-specific hydroxymethylcytosine patterns were determined through hydroxymethyl DNA immunoprecipitation array in hepatic DNA.
  
  
  RESULTS
  Hydroxymethylcytosine patterns were more perturbed by alcohol consumption in young mice than in old mice (431 differentially hydroxymethylated regions, DhMRs, in young vs 189 DhMRs in old). A CpG island ~2.5 kb upstream of the glucocorticoid receptor gene, Nr3c1, had increased hydroxymethylation as well as increased mRNA expression (p = 0.015) in young mice fed alcohol relative to the control group. Aging alone also altered hydroxymethylcytosine patterns, with 331 DhMRs, but alcohol attenuated this effect. Aging was associated with a decrease in hydroxymethylcytosine ~1 kb upstream of the leptin receptor gene, Lepr, and decreased transcription of this gene (p = 0.029). Nr3c1 and Lepr are both involved in hepatic lipid homeostasis and hepatosteatosis, which may create a carcinogenic environment.
  
  
  CONCLUSIONS
  These results suggest that the location of hydroxymethylcytosine in the genome is site specific and not random, and that changes in hydroxymethylation may play a role in the liver's response to aging and alcohol.
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.|Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Tammen
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.|Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
authors.forename: Lara K
authors.initials: LK
authors.lastname: Park
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.|Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Dolnikowski
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.|Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Ausman
authors.affiliation: University of Verona School of Medicine, Verona, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Friso
authors.affiliation: Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. sang.choi@cha.ac.kr.|Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA. sang.choi@cha.ac.kr.|Chaum Life Center, CHA University School of Medicine, 442, Dosan-daero, Gangnam-gu, Seoul, 135-948, Korea. sang.choi@cha.ac.kr.
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
mesh_terms: D000375:Aging / Q000378:metabolism*; D000428:Alcohol Drinking / Q000378:metabolism*; D000437:Alcoholism / Q000378:metabolism; D000818:Animals; D003596:Cytosine / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics; D053263:Gene Regulatory Networks; D006706:Homeostasis / Q000235:genetics; D006900:Hydroxylation / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054411:Receptors, Leptin / Q000235:genetics
chemical_list: D054411:Receptors, Leptin; D003596:Cytosine; D004247:DNA
keywords: Aging; Alcohol; DNA hydroxymethylation; Liver; hmeDIP-Chip