Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways

Serena Ghisletti; Wendy Huang; Kristen Jepsen; Chris Benner; Gary Hardiman; Michael G. Rosenfeld; Christopher K. Glass

doi:10.1101/gad.1773109

Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways

¹Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California 92093, USA;
²Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, California 92093, USA;
³Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA;
⁴Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093, USA;
⁵Bioinformatics Graduate Program, University of California at San Diego, La Jolla, California 92093, USA

Abstract

Innate immune responses to bacterial or viral infection require rapid transition of large cohorts of inflammatory response genes from poised/repressed to actively transcribed states, but the underlying repression/derepression mechanisms remain poorly understood. Here, we report that, while the nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors establish repression checkpoints on broad sets of inflammatory response genes in macrophages and are required for nearly all of the transrepression activities of liver X receptors (LXRs), they can be selectively recruited via c-Jun or the Ets repressor Tel, respectively, establishing NCoR-specific, SMRT-specific, and NCoR/SMRT-dependent promoters. Unexpectedly, the binding of NCoR and SMRT to NCoR/SMRT-dependent promoters is frequently mutually dependent, establishing a requirement for both proteins for LXR transrepression and enabling inflammatory signaling pathways that selectively target NCoR or SMRT to also derepress/activate NCoR/SMRT-dependent genes. These findings reveal a combinatorial, corepressor-based strategy for integration of inflammatory and anti-inflammatory signals that play essential roles in immunity and homeostasis.

Keywords

Footnotes

↵6 Present address: Department of Experimental Oncology, European Institute of Oncology, Via Adamello, 16, 20139 Milano, Italy.
↵7 Corresponding author.

↵E-MAIL ckg{at}ucsd.edu; FAX (858) 822-2127.
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1773109.
Supplemental material is available at http://www.genesdev.org.
- Received December 16, 2008.
- Accepted February 5, 2009.