title: Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo.
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.
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Hee-Woong
authors.initials: HW
authors.lastname: Lim
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), 13125 Berlin, Germany; Institute for Diabetes and Obesity, Helmholtz Zentrum München, 85748 Garching, Germany;
authors.forename: N Henriette
authors.initials: NH
authors.lastname: Uhlenhaut
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute Jena, D-07745 Jena, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute Jena, D-07745 Jena, Germany;
authors.forename: Juliane
authors.initials: J
authors.lastname: Weiner
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute Jena, D-07745 Jena, Germany; Institute for Comparative Molecular Endocrinology, University of Ulm, D-89081 Ulm, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: Hübner
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), 13125 Berlin, Germany;
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Department of Pharmacology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute Jena, D-07745 Jena, Germany; Institute for Comparative Molecular Endocrinology, University of Ulm, D-89081 Ulm, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.affiliation: The Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Steger
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D015870:Gene Expression; D015316:Genetic Therapy; D023281:Genomics / Q000379:methods*; D005938:Glucocorticoids / Q000494:pharmacology*; D059014:High-Throughput Nucleotide Sequencing; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors