title: Age-related loss of CpG methylation in the tumour necrosis factor promoter.
abstract: BACKGROUND
  Dysregulated production of TNF has been implicated in the pathogenesis and severity of inflammatory rheumatic diseases, many of which show age-related increased incidence. Ageing is also associated with changes in the immune system including higher systemic levels of pro-inflammatory cytokines. Methylation of DNA is an important regulator of gene expression and changes with age.
  
  
  OBJECTIVE
  In this study we investigated whether the DNA methylation status of the TNF promoter changed with age in peripheral blood leucocytes and macrophages.
  
  
  RESULTS
  Using pyrosequencing assays we detected age-related demethylation of CpG motifs (-304, -245 and -239) in the TNF promoter in human peripheral blood cells from 312 healthy controls (0.8% per decade, confidence interval (CI)=0.44-1.13%, p=1×10(-5)) and primary monocyte-derived macrophages (MDM) from a separate population of 78 healthy controls (1.4% per decade, CI=0.79-2.13%, p=7×10(-5)). Methylation a TNF promoter fragment (-345-+154) resulted in 78% reduction of reporter gene activity compared with the unmethylated promoter construct.
  
  
  CONCLUSIONS
  These data suggest a potential role of accrued changes in DNA methylation in the development of age-related inflammatory diseases, such as rheumatoid arthritis and polymyalgia rheumatica, in which TNF is a pivotal mediator.
authors: Department of Infection & Immunity, Medical School, University of Sheffield, Sheffield S10 2RX, United Kingdom.
authors: Isobel R
authors: IR
authors: Gowers
authors: Kevin
authors: K
authors: Walters
authors: Endre
authors: E
authors: Kiss-Toth
authors: Robert C
authors: RC
authors: Read
authors: Gordon W
authors: GW
authors: Duff
authors: Anthony G
authors: AG
authors: Wilson
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics*; D016384:Consensus Sequence / Q000235:genetics; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D059372:Nucleotide Motifs / Q000235:genetics; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha