Genome-wide analysis of SREBP1 activity around the clock reveals its combined dependency on nutrient and circadian signals

PLoS Genet. 2014 Mar 6;10(3):e1004155. doi: 10.1371/journal.pgen.1004155. eCollection 2014 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • CLOCK Proteins / genetics
  • Circadian Clocks / genetics*
  • Circadian Clocks / physiology
  • Circadian Rhythm / genetics*
  • Circadian Rhythm / physiology
  • Gene Expression Regulation
  • Genome
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Homeostasis
  • Lipid Metabolism / genetics*
  • Mice
  • Protein Binding
  • Sterol Regulatory Element Binding Protein 1 / genetics*

Substances

  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • CLOCK Proteins

Associated data

  • GEO/GSE48375

Grant support

The CycliX Consortium is supported by the Swiss SystemsX.ch (www.systemsx.ch) initiative evaluated by the Swiss National Science Foundation, Sybit, the SystemsX.ch IT unit, the University of Lausanne, the University of Geneva, the Ecole Polytechnique Fédérale de Lausanne (EPFL), and Vital-IT. This work was also supported by the Swiss National Science Foundation (Grant 31003A_135583 to BD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.