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ChIP-MS of GR and in mouse liver

ABSTRACT: The Glucocorticoid Receptor (GR) is a potent metabolic regulator and a major drug target. While GR was shown to play various important roles in circadian biology, its rhythmic genomic actions have never been studied. Here we mapped GR’s genome-wide chromatin occupancy in mouse livers throughout the day/night cycle. We show how GR partitions metabolic processes during fasting (cellular maintenance, gluconeogenesis) and feeding (lipid and amino acid metabolism) by time-dependent binding and target gene regulation. Highlighting the dominant role GR plays in synchronizing circadian pathways, we find that the majority of oscillating genes harbor GR binding sites and depend on GR for amplitude stability . Surprisingly, this rhythmic pattern is altered by exposure to high fat diet in a ligand-independent manner. We show how the remodeling of oscillatory gene expression and GR binding result from a concomitant increase with Stat5 co-occupancy in obese mice, and that loss of GR reduces circulating glucose and triglycerides differentially during feeding and fasting. Altogether, our findings highlight GR’s fundamental role in the rhythmic orchestration of hepatic metabolism.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Michael Wierer

LAB HEAD: Matthias Mann

PROVIDER: PXD014030 | Pride | 2019-10-24

REPOSITORIES: Pride

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			Action	DRS
	20180530_QX3_MiWi_SA_ST00_COLLAB_Fabiana_1.raw	Raw
	20180530_QX3_MiWi_SA_ST00_COLLAB_Fabiana_10.raw	Raw
	20180530_QX3_MiWi_SA_ST00_COLLAB_Fabiana_11.raw	Raw
	20180530_QX3_MiWi_SA_ST00_COLLAB_Fabiana_12.raw	Raw
	20180530_QX3_MiWi_SA_ST00_COLLAB_Fabiana_2.raw	Raw

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Insulin signaling and reduced glucocorticoid receptor activity attenuate post-prandial gene expression in liver

Project description:C57BL/6J mice were subjected to night restricted feeding (ZT12-ZT24) and livers were isolated immediate before (ZT10) and after feeding (ZT14). Combined RNA-seq, DNase-seq and H3K27Ac ChIP-seq identified hundreds of genes and enhancers regulated by acute feeding. Importantly, this feeding regulated transcriptional program follows similar rhythmic expression patterns as the intrinsic circadian transcriptional programs. ChIP-seq showed that feeding repressed enhancers were occupied by both GR and FOXO1 and occupancy of these factors were suppressed by feeding correlating with increased insulin levels and reduced corticosterone levels. Interestingly, despite considerable genome-wide overlap between GR and FOXO1, injection of dexamethasone (dex) or insulin receptor antagonist (S961) immediately before feeding, demonstrated that the glucocorticoid and insulin receptor pathways control distinct transcriptional programs. And strikingly, only combined dex and S961 treatment reversed feeding induced changes to most of the hepatic transcriptome. These corticosteroid and insulin regulated transcriptional programs are dysregulated in diet-induced obese animals.

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Project description:Glucocorticoids (GCs) are widely prescribed effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a ligand-gated transcription factor. The transcriptional activation of metabolic genes by GR is thought to underlie these undesired adverse effects. Using mouse genetics, ChIP-Seq, RNA-Seq and ChIP-MS, we found that the bHLH transcription factor E47 is required for the regulation of hepatic glucose and lipid metabolism by GR in vivo, and that loss of E47 prevents the development of hyperglycemia and hepatic steatosis in response to GCs. Here we show that E47 and GR co-occupy metabolic promoters and enhancers. E47 is needed for the efficient binding of GR to chromatin and for the adequate recruitment of coregulators such as Mediator. Taken together, our results illustrate how GR and E47 regulate hepatic metabolism, and how inhibition of E47 might provide an entry point for novel GC therapies with reduced side effect profiles. These ChIP-MS data sets show IPs for GR in both wildtype and E47 mutant mouse livers treated with the synthetic glucocorticoid Dexamethasone.

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