Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

  1. David J. Steger1,8
  1. 1The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
  2. 2Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
  3. 3Max Delbrück Center for Molecular Medicine (MDC), 13125 Berlin, Germany;
  4. 4Institute for Diabetes and Obesity, Helmholtz Zentrum München, 85748 Garching, Germany;
  5. 5Leibniz Institute for Age Research - Fritz Lipmann Institute Jena, D-07745 Jena, Germany;
  6. 6Institute for Comparative Molecular Endocrinology, University of Ulm, D-89081 Ulm, Germany;
  7. 7Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
  8. 8Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
  1. Corresponding authors: stegerdj{at}mail.med.upenn.edu, jan.tuckermann{at}uni-ulm.de, henriette.uhlenhaut{at}helmholtz-muenchen.de
  1. 9 These authors contributed equally to this work.

  • 10 Present address: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark

Abstract

Glucocorticoids (GCs) are commonly prescribed drugs, but their anti-inflammatory benefits are mitigated by metabolic side effects. Their transcriptional effects, including tissue-specific gene activation and repression, are mediated by the glucocorticoid receptor (GR), which is known to bind as a homodimer to a palindromic DNA sequence. Using ChIP-exo in mouse liver under endogenous corticosterone exposure, we report here that monomeric GR interaction with a half-site motif is more prevalent than homodimer binding. Monomers colocalize with lineage-determining transcription factors in both liver and primary macrophages, and the GR half-site motif drives transcription, suggesting that monomeric binding is fundamental to GR's tissue-specific functions. In response to exogenous GC in vivo, GR dimers assemble on chromatin near ligand-activated genes, concomitant with monomer evacuation of sites near repressed genes. Thus, pharmacological GCs mediate gene expression by favoring GR homodimer occupancy at classic palindromic sites at the expense of monomeric binding. The findings have important implications for improving therapies that target GR.

Footnotes

  • Received December 16, 2014.
  • Accepted April 13, 2015.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

| Table of Contents

Preprint Server