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Glucocorticoid Receptor-Mediated Repression of Pro-Inflammatory Genes in Rheumatoid Arthritis

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Technical Report,20 Sep 2014,19 Sep 2015

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Hospital For Special Surgery Fund New York United States

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Most rheumatoid arthritis RA patients rely on glucocorticoids GCs at some point during the disease. GCs signal through the GC receptorGR, a transcription factor that in addition to binding DNA directly can tether to DNA-bound AP1 and NFkB and repress their numerous pro-inflammatory target genes. We discovered that GR-Interacting Protein GRIP1 in macrophages M serves as a novel GR corepressor. Notably, GRGRIP1 complexes repress pro-inflammatory genes of two classes those activated through RNA polymerasePolII recruitment and transcription initiation and others, pre-loaded with paused Pol II that requires a signal for entry into productive elongation. We aim to dissect the role of M GRIP1 as a driver of anti-inflammatory actions of GCs at the level of GR transcription complexes at genes of each regulatory class and in mouse models of RA. Having established technologies to identify GRGRIP1-regulatedgenes in M genome-wide, we are creating cistromes of where GR, GRIP1 and Pol II bind in inflammatory and GC-treated M. We have made a substantial progress in understanding mechanistically how GRGRIP1 repress pro-inflammatory genes of different classes. Using representative genes of each class, we are able to dissect the differences in step-wise assembly of the activation complexes that become targets for GR repression.

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