title: Effects of Sirt1 on DNA methylation and expression of genes affected by dietary restriction.
abstract: Changes in DNA methylation across the life course may contribute to the ageing process. We hypothesised that some effects of dietary restriction to extend lifespan and/or mitigate against features of ageing result from changes in DNA methylation, so we determined if genes that respond to dietary restriction also show age-related changes in DNA methylation. In support of our hypothesis, the intersection of lists of genes compiled from published sources that (1) were differentially expressed in response to dietary restriction and (2) showed altered methylation with increased age was greater than expected. We also hypothesised that some effects of Sirt1, which may play a pivotal role in beneficial effects of dietary restriction, are mediated through DNA methylation. We thus measured effects of Sirt1 overexpression and knockdown in a human cell line on DNA methylation and expression of a panel of eight genes that respond to dietary restriction and show altered methylation with age. Six genes were affected at the level of DNA methylation, and for six expressions were affected. In further support of our hypothesis, we observed by DNA microarray analysis that genes showing differential expression in response to Sirt1 knockdown were over-represented in the complied list of genes that respond to dietary restriction. The findings reveal that Sirt1 has effects on DNA methylation across the genome and affects, in particular, the expression of genes that respond to dietary restriction. Sirt1-mediated effects on DNA methylation and, consequently, gene expression may thus be one of the mechanisms underlying the response to dietary restriction.
authors.affiliation: Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Ions
authors.forename: Luisa A
authors.initials: LA
authors.lastname: Wakeling
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Bosomworth
authors.forename: Joy E J
authors.initials: JE
authors.lastname: Hardyman
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Escolme
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Swan
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Valentine
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
authors.forename: Dianne
authors.initials: D
authors.lastname: Ford
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects*; D004038:Diet, Reducing / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004247:DNA; C447939:SIRT1 protein, human; D056564:Sirtuin 1