51. Genome-Wide Analysis of SREBP1 Activity around the Clock Reveals Its Combined Dependency on Nutrient and Circadian Signals
- Author
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Felix Naef, Bart Deplancke, Laura Symul, Dmitry Kuznetsov, Aurélien Naldi, Winship Herr, Ioannis Xenarios, Nouria Hernandez, Federica Gilardi, Nicolas GUEX, Beatrice Desvergne, Guillaume Rey, CycliX Consortium, Hernandez, N., Delorenzi, M., Deplancke, B., Desvergne, B., Guex, N., Herr, W., Naef, F., Rougemont, J., Schibler, U., Andersin, T., Cousin, P., Gilardi, F., Gos, P., Martelot, G., Lammers, F., Canella, D., Raghav, S., Fabbretti, R., Fortier, A., Long, L., Vlegel, V., Xenarios, I., Migliavacca, E., Praz, V., David, F., Jarosz, Y., Kuznetsov, D., Liechti, R., Martin, O., Delafontaine, J., Sinclair, L., Cajan, J., Krier, I., Leleu, M., Molina, N., Naldi, A., Rey, G., Symul, L., Bernasconi, D., Baruchet, M., University of Zurich, and Guex, Nicolas
- Subjects
2716 Genetics (clinical) ,Cancer Research ,lcsh:QH426-470 ,SX20 Research, Technology and Development Projects ,Circadian clock ,CLOCK Proteins ,Biology ,Mice ,SX00 SystemsX.ch ,1311 Genetics ,Circadian Clocks ,1312 Molecular Biology ,Genetics ,Transcriptional regulation ,Animals ,Homeostasis ,1306 Cancer Research ,Circadian rhythm ,SX04 CycliX ,Molecular Biology ,Transcription factor ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,Regulation of gene expression ,Binding Sites ,Genome ,Lipid Metabolism ,Bacterial circadian rhythms ,Circadian Rhythm ,Sterol regulatory element-binding protein ,Cell biology ,lcsh:Genetics ,1105 Ecology, Evolution, Behavior and Systematics ,Gene Expression Regulation ,Hepatocyte Nuclear Factor 4 ,570 Life sciences ,biology ,Sterol Regulatory Element Binding Protein 1 ,Protein Binding ,Research Article - Abstract
In mammals, the circadian clock allows them to anticipate and adapt physiology around the 24 hours. Conversely, metabolism and food consumption regulate the internal clock, pointing the existence of an intricate relationship between nutrient state and circadian homeostasis that is far from being understood. The Sterol Regulatory Element Binding Protein 1 (SREBP1) is a key regulator of lipid homeostasis. Hepatic SREBP1 function is influenced by the nutrient-response cycle, but also by the circadian machinery. To systematically understand how the interplay of circadian clock and nutrient-driven rhythm regulates SREBP1 activity, we evaluated the genome-wide binding of SREBP1 to its targets throughout the day in C57BL/6 mice. The recruitment of SREBP1 to the DNA showed a highly circadian behaviour, with a maximum during the fed status. However, the temporal expression of SREBP1 targets was not always synchronized with its binding pattern. In particular, different expression phases were observed for SREBP1 target genes depending on their function, suggesting the involvement of other transcription factors in their regulation. Binding sites for Hepatocyte Nuclear Factor 4 (HNF4) were specifically enriched in the close proximity of SREBP1 peaks of genes, whose expression was shifted by about 8 hours with respect to SREBP1 binding. Thus, the cross-talk between hepatic HNF4 and SREBP1 may underlie the expression timing of this subgroup of SREBP1 targets. Interestingly, the proper temporal expression profile of these genes was dramatically changed in Bmal1 −/− mice upon time-restricted feeding, for which a rhythmic, but slightly delayed, binding of SREBP1 was maintained. Collectively, our results show that besides the nutrient-driven regulation of SREBP1 nuclear translocation, a second layer of modulation of SREBP1 transcriptional activity, strongly dependent from the circadian clock, exists. This system allows us to fine tune the expression timing of SREBP1 target genes, thus helping to temporally separate the different physiological processes in which these genes are involved., Author Summary Circadian rhythmicity is part of our innate behavior and controls many physiological processes, such as sleeping and waking, activity, neurotransmitter production and a number of metabolic pathways. In mammals, the central circadian pacemaker in the hypothalamus is entrained on a daily basis by environmental cues (i.e. light), thus setting the period length and synchronizing the rhythms of all cells in the body. In the last decades, numerous investigations have highlighted the importance of the internal timekeeping mechanism for maintenance of organism health and longevity. Indeed, the reciprocal regulation of circadian clock and metabolism is now commonly accepted, although still poorly understood at the molecular level. Our global analysis of DNA binding along the day of Sterol Regulatory Element Binding Protein 1 (SREBP1), a key regulator of lipid biosynthesis, represents the first tool to comprehensively explore how its activity is connected to circadian-driven regulatory events. We show that the regulation of SREBP1 action by nutrients relies mainly on the control of its subcellular localization, while the circadian clock influences the promoter specific activity of SREBP1 within the nucleus. Furthermore, we identify the Hepatocyte Nuclear Factor 4 (HNF4) as a putative player in the cross-talk between molecular clock and metabolic regulation.
- Published
- 2014