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

TY - JOUR

T1 - Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo

AU - Lim, Hee-Woong

AU - Uhlenhaut, N Henriette

AU - Rauch, Alexander

AU - Weiner, Juliane

AU - Hübner, Sabine

AU - Hübner, Norbert

AU - Won, Kyoung-Jae

AU - Lazar, Mitchell A

AU - Tuckermann, Jan

AU - Steger, David J

N1 - © 2015 Lim et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Chromatin/genetics

KW - Chromatin Immunoprecipitation

KW - Cloning, Molecular

KW - Gene Expression

KW - Genetic Therapy

KW - Genomics/methods

KW - Glucocorticoids/pharmacology

KW - High-Throughput Nucleotide Sequencing

KW - Liver/drug effects

KW - Macrophages/drug effects

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Receptors, Glucocorticoid/genetics

KW - Sequence Analysis, RNA

KW - Transcription Factors/genetics

KW - Transcriptional Activation

U2 - 10.1101/gr.188581.114

DO - 10.1101/gr.188581.114

M3 - Journal article

C2 - 25957148

SN - 1088-9051

VL - 25

SP - 836

EP - 844

JO - Genome Research

JF - Genome Research

IS - 6

ER -