Publication Date:
2015-06-06
Description:
Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbalpha, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbalpha modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbalpha to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbalpha regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erbalpha and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erbalpha uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613749/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613749/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Yuxiang -- Fang, Bin -- Emmett, Matthew J -- Damle, Manashree -- Sun, Zheng -- Feng, Dan -- Armour, Sean M -- Remsberg, Jarrett R -- Jager, Jennifer -- Soccio, Raymond E -- Steger, David J -- Lazar, Mitchell A -- F30 DK104513/DK/NIDDK NIH HHS/ -- F32 DK102284/DK/NIDDK NIH HHS/ -- K08 DK094968/DK/NIDDK NIH HHS/ -- P30 DK019525/DK/NIDDK NIH HHS/ -- P30 DK050306/DK/NIDDK NIH HHS/ -- P30 DK19525/DK/NIDDK NIH HHS/ -- R00 DK099443/DK/NIDDK NIH HHS/ -- R01 DK045586/DK/NIDDK NIH HHS/ -- R01 DK098542/DK/NIDDK NIH HHS/ -- R01 DK45586/DK/NIDDK NIH HHS/ -- T32 GM0008275/GM/NIGMS NIH HHS/ -- T32 GM008275/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1488-92. doi: 10.1126/science.aab3021. Epub 2015 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Molecular and Cellular Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. ; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Department of Genetics, and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. lazar@mail.med.upenn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26044300" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
CLOCK Proteins/*genetics
;
Circadian Clocks/*genetics
;
Circadian Rhythm/*genetics
;
*Gene Expression Regulation
;
Hepatocyte Nuclear Factor 6/metabolism
;
Histone Deacetylases/*metabolism
;
Lipid Metabolism/genetics
;
Liver/metabolism
;
Male
;
Metabolism/*genetics
;
Mice, Inbred C57BL
;
Mice, Knockout
;
Nuclear Receptor Subfamily 1, Group D, Member 1/genetics/*metabolism
;
Nuclear Receptor Subfamily 1, Group F, Member 1/metabolism
;
Organ Specificity
;
Protein Binding
;
Tissue Distribution
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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