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Age-related loss of CpG methylation in the tumour necrosis factor promoter

Gowers, I.R., Walters, K., Kiss-Toth, E., Read, R.C., Duff, G.W. and Wilson, A.G. (2011) Age-related loss of CpG methylation in the tumour necrosis factor promoter. Cytokine, 56 (3). pp. 792-797. ISSN 1043-4666

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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.

Methods and 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 x 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 x 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. (C) 2011 Elsevier Ltd. All rights reserved.

Item Type: Article
Copyright, Publisher and Additional Information: © 2011 Elsevier. This is an author produced version of a paper subsequently published in Cytokine. Uploaded in accordance with the publisher's self-archiving policy.
Keywords: DNA methylation; Age; TNF; Expression; Epigenetics
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Department of Infection & Immunity
Depositing User: Miss Anthea Tucker
Date Deposited: 27 Jan 2012 15:30
Last Modified: 08 Feb 2013 17:36
Published Version: http://dx.doi.org/10.1016/j.cyto.2011.09.009
Status: Published
Publisher: Elsevier
Refereed: Yes
Identification Number: 10.1016/j.cyto.2011.09.009
URI: http://eprints.whiterose.ac.uk/id/eprint/43687

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