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.
Highlights
Mammals possess an internal circadian clock which allows them to anticipate and adapt to daily environmental changes [1]
The molecular mechanism underlying the cell-autonomous circadian rhythms relies on a network of feedback loops in which BMAL1, CLOCK, Neuronal PAS domain (NPAS) protein 2 and Retinoic acid receptor-related Orphan Receptor (ROR) proteins act as transcriptional activators and period homolog proteins (PER1, 2 and 3), cryptochromes (CRY1 and 2) and REV-ERBs function as inhibitors producing the self-sustained oscillating production of their target genes, including themselves
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
Summary
Mammals possess an internal circadian clock which allows them to anticipate and adapt to daily environmental changes [1]. In peripheral organs such as the liver, oscillations are entrained by the feeding and fasting cycle [2,3,4]. This sophisticated regulatory system contributes to coordinate many physiological processes, such as sleep-wake cycles, locomotor activity, body temperature, hormone secretion and energy metabolism that all display circadian rhythms. In genetic mouse models the disruption of the clock alters metabolic homeostasis at different levels (reviewed in [8]), suggesting a still unresolved relationship between nutrient state and circadian homeostasis
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