Circadian rhythms dominate a large array of physiological, biochemical and behavioral responses in most living organisms. The circadian clock is an intrinsic time-tracking system that enables the adaptation to environmental changes. Disruption of circadian rhythms has profound influence to human health and has been linked to depression, sleep disorders, coronary heart disease, metabolic disturbances, neurodegenerative diseases and cancer. Thereby, the molecular mechanisms governing the circadian clock constitute a very attractive hold for the understanding of the links to physiology and metabolism, representing potential tools for the development of therapeutic strategies. Remarkably, 10-15% of all mammalian transcripts undergo circadian fluctuations in their expression levels. Thus, genome-wide mechanisms must operate in order to insure such global transcriptional regulation. Our recent studies (Cell (2006) 125: 497-508;Nature (2007) 450, 1086-90;Cell (2008) in press) have established that CLOCK, a master regulator of circadian rhythms, directly acetylates histones and its partner BMAL1. CLOCK intrinsic HAT enzymatic activity demonstrates that control of chromatin remodeling constitutes a key regulatory step governing the circadian clock machinery. In a search for non-histone substrates of CLOCK, we have explored the possibility that nuclear receptors could be acetylated in a circadian manner. This possibility is supported by the presence of a putative NRID (nuclear receptor interaction domain) in CLOCK and by the intimate links that exist between circadian physiology and regulation of metabolism by some distinct nuclear receptors. Our preliminary studies have identified HNF-4 as a privileged CLOCK target. This proposal is centered on deciphering the molecular, functional and physiological significance of this event. HNF-4 is a nuclear receptor which controls liver metabolism and hepatocyte differentiation. Its activity may be modulated by the binding of fatty acid acyl-CoA thioesters and has been linked to the control of glucose metabolism and, indirectly, to xenobiotic metabolism. Thus, we have identified a molecular link that has multiple molecular and physiological implications and paves the way to a number of important in vitro and in vivo studies. We predict that these studies will provide novel and important insights into how circadian physiology and metabolism are controlled by epigenetic processes.

Public Health Relevance

The circadian clock governs a large variety of our rhythmic physiology, including sleep-wake cycles, metabolism and hormonal levels. This proposal is aimed at deciphering the intimate mechanisms by which the circadian clock controls a key player in liver metabolism, the nuclear receptor HNF4. These studies will provide novel and important insights into how circadian physiology and metabolism are controlled by epigenetic processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG033888-02
Application #
7769499
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Murthy, Mahadev
Project Start
2009-03-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$155,257
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Abbondante, Serena; Eckel-Mahan, Kristin L; Ceglia, Nicholas J et al. (2016) Comparative Circadian Metabolomics Reveal Differential Effects of Nutritional Challenge in the Serum and Liver. J Biol Chem 291:2812-28
de Mateo, Sara; Sassone-Corsi, Paolo (2014) Regulation of spermatogenesis by small non-coding RNAs: role of the germ granule. Semin Cell Dev Biol 29:84-92
Eckel-Mahan, Kristin L; Patel, Vishal R; de Mateo, Sara et al. (2013) Reprogramming of the circadian clock by nutritional challenge. Cell 155:1464-78
Aguilar-Arnal, Lorena; Hakim, Ofir; Patel, Vishal R et al. (2013) Cycles in spatial and temporal chromosomal organization driven by the circadian clock. Nat Struct Mol Biol 20:1206-13
Eckel-Mahan, Kristin; Sassone-Corsi, Paolo (2013) Metabolism and the circadian clock converge. Physiol Rev 93:107-35
Patel, Vishal R; Eckel-Mahan, Kristin; Sassone-Corsi, Paolo et al. (2012) CircadiOmics: integrating circadian genomics, transcriptomics, proteomics and metabolomics. Nat Methods 9:772-3
Sahar, Saurabh; Sassone-Corsi, Paolo (2012) Regulation of metabolism: the circadian clock dictates the time. Trends Endocrinol Metab 23:1-8
Eckel-Mahan, Kristin L; Patel, Vishal R; Mohney, Robert P et al. (2012) Coordination of the transcriptome and metabolome by the circadian clock. Proc Natl Acad Sci U S A 109:5541-6
Bellet, Marina M; Vawter, Marquis P; Bunney, Blynn G et al. (2011) Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression. PLoS One 6:e23982
Masubuchi, Satoru; Gao, Tianyan; O'Neill, Audrey et al. (2010) Protein phosphatase PHLPP1 controls the light-induced resetting of the circadian clock. Proc Natl Acad Sci U S A 107:1642-7

Showing the most recent 10 out of 13 publications