Glucocorticoid Receptor-Mediated Repression of Pro-Inflammatory Genes in Rheumatoid Arthritis
Abstract
Most rheumatoid arthritis (RA) patients rely on glucocorticoids (GCs) at some point during the disease. GCs signal through the GC receptor(GR), 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 (GRIP)1 in macrophages (M) serves as a novel GR corepressor. Notably, GR:GRIP1 complexes repress pro-inflammatory genes of two classes: those activated through RNA polymerase(Pol)II 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 GR:GRIP1-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 GR:GRIP1 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1012229
Entities
People
- Inez Rogatsky
Organizations
- Hospital for Special Surgery