Chromatin recruitment of activated AMPK drives fasting response genes co-controlled by GR and PPARα. Issue 22 (30th August 2016)

• Record Type: Journal Article
• Authors: Ratman, Dariusz; Mylka, Viacheslav; Bougarne, Nadia; Pawlak, Michal; Caron, Sandrine; Hennuyer, Nathalie; Paumelle, Réjane; De Cauwer, Lode; Thommis, Jonathan; Rider, Mark H.; Libert, Claude; Lievens, Sam; Tavernier, Jan; Staels, Bart; De Bosscher, Karolien
• Is Part Of: Nucleic acids research. Volume 44:Issue 22(2016)
• Page Start: 10539
• Page End: 10553
• Publication Date: 2016-08-30
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkw742
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Adaptation to fasting involves both Glucocorticoid Receptor (GRα) and Peroxisome Proliferator-Activated Receptor α (PPARα) activation. Given both receptors can physically interact we investigated the possibility of a genome-wide cross-talk between activated GR and PPARα, using ChIP- and RNA-seq in primary hepatocytes. Our data reveal extensive chromatin co-localization of both factors with cooperative induction of genes controlling lipid/glucose metabolism. Key GR/PPAR co-controlled genes switched from transcriptional antagonism to cooperativity when moving from short to prolonged hepatocyte fasting, a phenomenon coinciding with gene promoter recruitment of phosphorylated AMP-activated protein kinase (AMPK) and blocked by its pharmacological inhibition. In vitro interaction studies support trimeric complex formation between GR, PPARα and phospho-AMPK. Long-term fasting in mice showed enhanced phosphorylation of liver AMPK and GRα Ser211. Phospho-AMPK chromatin recruitment at liver target genes, observed upon prolonged fasting in mice, is dampened by refeeding. Taken together, our results identify phospho-AMPK as a molecular switch able to cooperate with nuclear receptors at the chromatin level and reveal a novel adaptation mechanism to prolonged fasting.