Genome-Wide Analysis of SREBP1 Activity around the Clock Reveals Its Combined Dependency on Nutrient and Circadian Signals

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.

Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding–fasting response and the circadian clock

“…S3C). Cluster 3 included 331 genes that peaked at the end of the day (ZT10) and were associated with steroid metabolic processes, as previously reported (Edwards et al 1972;Matsumoto et al 2010;Gilardi et al 2014), as well as glycogen metabolic process, circadian regulation of gene expression, circadian rhythm, and rhythmic processes. The rhythmic expression of these genes was altered in both CF mice and Arntl KO mice, although to a greater extent in the latter, as illustrated by blurring of the clusters (Fig.…”

Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP

“…A previous study had uncovered ~400 SREBP1 binding sites (Gilardi et al, 2014), 15–20% of which overlapped with HDAC3 binding sites in mouse liver (Feng et al, 2011). Since HDAC3 and SREBP have opposing effects on lipid metabolism, this raised the question of whether SREBP might interfere with HDAC3 binding.…”

Circadian Enhancers Coordinate Multiple Phases of Rhythmic Gene Transcription In Vivo

“…Some of these TFs, such as CREB and SREBP, bind preferentially to promoters of target genes (Everett et al, 2013; Gilardi et al, 2014; Seo et al, 2009), which would not be captured by analysis of eRNAs. Phase-specific enrichment could also have been masked by motifs bound by constitutive liver TFs, such as HNF4A and FOXA1, that bind at enhancers in all phases.…”