Open Access Research article

Glucocorticoid receptor coordinates transcription factor-dominated regulatory network in macrophages

Yurii Chinenov14*, Maddalena Coppo1, Rebecca Gupte2, Maria A Sacta3 and Inez Rogatsky124*

Author Affiliations

1 Hospital for Special Surgery, The David Rosensweig Genomics Center, 535 East 70th Street, New York, NY 10021, USA

2 Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10021, USA

3 Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, 1300 York Avenue, New York, NY 10021, USA

4 Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10021, USA

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BMC Genomics 2014, 15:656  doi:10.1186/1471-2164-15-656

Published: 6 August 2014

Abstract

Background

Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of transcriptional responses to GR activation and the molecular basis of their oftentimes non-linear dynamics are not understood.

Results

We investigated early glucocorticoid-driven transcriptional events in macrophages, a cell type highly responsive to both pro- and anti-inflammatory stimuli. Using whole transcriptome analyses in resting and acutely lipopolysaccharide (LPS)-stimulated macrophages, we show that early GR target genes form dense networks with the majority of control nodes represented by transcription factors. The expression dynamics of several glucocorticoid-responsive genes are consistent with feed forward loops (FFL) and coincide with rapid GR recruitment. Notably, GR binding sites in genes encoding members of the KLF transcription factor family colocalize with KLF binding sites. Moreover, our gene expression, transcription factor binding and computational data are consistent with the existence of the GR-KLF9-KLF2 incoherent FFL. Analysis of LPS-downregulated genes revealed striking enrichment in multimerized Zn-fingers- and KRAB domain-containing proteins known to bind nucleic acids and repress transcription by propagating heterochromatin. This raises an intriguing possibility that an increase in chromatin accessibility in inflammatory macrophages results from broad downregulation of negative chromatin remodelers.

Conclusions

Pro- and anti-inflammatory stimuli alter the expression of a vast array of transcription factors and chromatin remodelers. By regulating multiple transcription factors, which propagate the initial hormonal signal, GR acts as a coordinating hub in anti-inflammatory responses. As several KLFs promote the anti-inflammatory program in macrophages, we propose that GR and KLFs functionally cooperate to curb inflammation.

Keywords:
Transcriptional regulation; Glucocorticoid receptor; Inflammation; Feed forward loops; Gene regulatory network; KLF transcription factors