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

Official URL:https://doi.org/10.1101/gr.188581.114
PubMed:View item in PubMed
Creators Name:Lim, H.W. and Uhlenhaut, N.H. and Rauch, A. and Weiner, J. and Huebner, S. and Huebner, N. and Won, K.J. and Lazar, M.A. and Tuckermann, J. and Steger, D.J.
Journal Title:Genome Research
Journal Abbreviation:Genome Res
Volume:25
Number:6
Page Range:836-844
Date:June 2015
Keywords:Chromatin, Chromatin Immunoprecipitation, Cultured Cells, Gene Expression, Genetic Therapy, Genomics, Glucocorticoid Receptors, Glucocorticoids, High-Throughput Nucleotide Sequencing, Inbred BALB C Mice, Liver, Macrophages, Molecular Cloning, RNA Sequence Analysis, Transcription Factors, Transcriptional Activation, Animals, Mice
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.
ISSN:1088-9051
Publisher:Cold Spring Harbor Laboratory Press (U.S.A.)
Item Type:Article

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