Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism

Selma Masri; Paul Rigor; Marlene Cervantes; Nicholas Ceglia; Carlos Sebastian; Cuiying Xiao; Manuel Roqueta-Rivera; Chuxia Deng; Timothy F Osborne; Raul Mostoslavsky; Pierre Baldi; Paolo Sassone-Corsi

doi:10.1016/j.cell.2014.06.050

Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism

Cell. 2014 Jul 31;158(3):659-72. doi: 10.1016/j.cell.2014.06.050.

Authors

Affiliations

¹ Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
² Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA; Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA 92697, USA.
³ The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
⁴ Genetics of Development and Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Metabolic Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
⁶ Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Department of Computer Science, University of California, Irvine, Irvine, CA 92697, USA; Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA 92697, USA.
⁷ Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA; Institute for Genomics and Bioinformatics, University of California, Irvine, Irvine, CA 92697, USA; INSERM U904, Sprague Hall, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: psc@uci.edu.

Abstract

Circadian rhythms are intimately linked to cellular metabolism. Specifically, the NAD(+)-dependent deacetylase SIRT1, the founding member of the sirtuin family, contributes to clock function. Whereas SIRT1 exhibits diversity in deacetylation targets and subcellular localization, SIRT6 is the only constitutively chromatin-associated sirtuin and is prominently present at transcriptionally active genomic loci. Comparison of the hepatic circadian transcriptomes reveals that SIRT6 and SIRT1 separately control transcriptional specificity and therefore define distinctly partitioned classes of circadian genes. SIRT6 interacts with CLOCK:BMAL1 and, differently from SIRT1, governs their chromatin recruitment to circadian gene promoters. Moreover, SIRT6 controls circadian chromatin recruitment of SREBP-1, resulting in the cyclic regulation of genes implicated in fatty acid and cholesterol metabolism. This mechanism parallels a phenotypic disruption in fatty acid metabolism in SIRT6 null mice as revealed by circadian metabolome analyses. Thus, genomic partitioning by two independent sirtuins contributes to differential control of circadian metabolism.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

ARNTL Transcription Factors / metabolism
Animals
CLOCK Proteins / metabolism
Chromatin
Circadian Rhythm
Gene Expression Profiling
Liver / metabolism*
Mice
Mice, Knockout
Sirtuin 1 / genetics
Sirtuin 1 / metabolism
Sirtuins / genetics
Sirtuins / metabolism*
Transcription, Genetic

Substances

ARNTL Transcription Factors
Bmal1 protein, mouse
Chromatin
CLOCK Proteins
Clock protein, mouse
Sirt6 protein, mouse
Sirt1 protein, mouse
Sirtuin 1
Sirtuins

Associated data

GEO/GSE57830

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding