title: Nicotinamide treatment reduces the levels of histone H3K4 trimethylation in the promoter of the mper1 circadian clock gene and blocks the ability of dexamethasone to induce the acute response.
abstract: Circadian rhythms, which measure time on a scale of 24h, are generated by one of the most ubiquitous endogenous mechanisms, the circadian clock. SIRT1, a class III histone deacetylase, and PARP-1, a poly(ADP-ribose) polymerase, are two NAD(+)-dependent enzymes that have been shown to be involved in the regulation of the clock. Here we present evidence that the metabolite nicotinamide, an inhibitor of SIRT1, PARP-1 and mono(ADP-ribosyl) transferases, blocks the ability of dexamethasone to induce the acute response of the circadian clock gene, mper1, while it concomitantly reduces the levels of histone H3 trimethylation of lysine 4 (H3K4me3) in the mper1 promoter. Moreover, application of alternative inhibitors of SIRT1 and ADP-ribosylation did not lead to similar results. Therefore, inhibition of these enzymes does not seem to be the mode by which NAM exerts these effects. These results suggest the presence of a novel mechanism, not previously documented, by which NAM can alter gene expression levels via changes in the histone H3K4 trimethylation state.
authors.affiliation: Institute of Biology, National Center for Scientific Research, Attiki, Greece. mxidous@yahoo.com
authors.forename: M
authors.initials: M
authors.lastname: Xydous
authors.forename: K E
authors.initials: KE
authors.lastname: Sekeri-Pataryas
authors.forename: A
authors.initials: A
authors.lastname: Prombona
authors.forename: T G
authors.initials: TG
authors.lastname: Sourlingas
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000187:drug effects / Q000235:genetics; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009536:Niacinamide / Q000378:metabolism / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D056950:Period Circadian Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009536:Niacinamide; D003907:Dexamethasone; D010089:Oxidoreductases, N-Demethylating; C544113:kdm1b protein, mouse; D011065:Poly(ADP-ribose) Polymerases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1