Abstract
Glucocorticoids (GCs) are 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 transcription factor. The activation of metabolic genes by GR is thought to underlie these adverse effects. We identify the bHLH factor E47 as a modulator of GR target genes. Using mouse genetics, we find that E47 is required for the regulation of hepatic glucose and lipid metabolism by GR, 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 recruitment of GR and coregulators such as Mediator to chromatin. Altogether, our results illustrate how GR and E47 regulate hepatic metabolism, and might provide an entry point for novel therapies with reduced side effects.
Highlights
Glucocorticoids (GCs) are effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity
Glucocorticoid Receptor (GR) is a nuclear receptor known to bind to consensus DNA sequences termed glucocorticoid response elements (GREs), but the exact mechanisms leading to transcriptional activation versus repression are unclear[3,4,5]
We find that co-occupancy of GR and E47 on a subset of liver enhancers is required for effective loading of the Mediator complex and transcriptional activation of metabolic gene expression by GR and FoxO1 in response to GCs
Summary
Glucocorticoids (GCs) are effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. E47 is mostly known for its role in B and T cell lineage commitment, it is expressed in many tissues[10,11] It is encoded by the E2A or Tcf[3] gene, and together with E12 (which arises from the same E2A gene by alternative splicing), E2–2 and HEB belongs to the class of E proteins that can heterodimerize with other bHLH factors. These E proteins are inhibited by binding to ID (Inhibitor of DNA binding) proteins, and this interplay is necessary to drive tissue and cell type specific gene expression programs. Mutation of all four ID proteins in mice has been linked to phenotypic alterations in glucose, lipid and cholesterol metabolism[12]
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