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Science 331 (6022): 1315-1319

Copyright © 2011 by the American Association for the Advancement of Science

A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism

Dan Feng,1,* Tao Liu,2,* Zheng Sun,1 Anne Bugge,1 Shannon E. Mullican,1 Theresa Alenghat,1 X. Shirley Liu,2 Mitchell A. Lazar1,{dagger}

Abstract: Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis.

1 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism (IDOM), University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
2 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02115, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: lazar{at}mail.med.upenn.edu


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