title: Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging.
abstract: Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.|Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rui-Hong
authors.initials: RH
authors.lastname: Wang
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tingrui
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: Kairong
authors.initials: K
authors.lastname: Cui
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: Gangqing
authors.initials: G
authors.lastname: Hu
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Genomic Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Chen
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xin-Wei
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto-Gutierrez
authors.affiliation: Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.|Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002940:Circadian Rhythm; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C421902:PER2 protein, human; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1