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Epigenetic regulation of chronic inflammatory diseases

Tuesday 12 January 2016

Project
Genetic factors make significant but incomplete contributions to the development and persistence of pathology in many chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), systemic sclerosis (SSc), and lupus (SLE). Epigenetic influences, which modify DNA and histones to regulate gene expression are now known to interact with genetic backgrounds to contribute to these diseases. In this project line, in cooperation with Prof. Dr. Tim Radstake and Dr. Marzia Rossato, we examine changes in the expression and activity of epigenetic regulatory proteins, such as histone deacetlyases (HDACs), and reader proteins which interpret the epigenetic code in isolated white blood cells and stromal cells from affected tissues from patients with various immune-mediated inflammatory diseases. We then use overexpression studies, gene silencing, and novel pharmacological compounds to modify the function of these epigenetic regulatory proteins and assess their effects on cellular function and gene expression. In the future, we will examine how the dynamic regulation of these epigenetic regulatory proteins impacts upon patient responses to treatment in prospective clinical studies.

Techniques
Flow cytometry, RNA-seq, qPCR, immunoblotting, adenoviral expression, gene silencing, invasion assays, ELISA, tissue cell isolation, cell-cell interaction assays

Duration
6 or 9 months

Contact
Kris Reedquist, k.a.reedquist@umcutrecht.nl

References
1. Grabiec AM, Korchynskyi O, Tak PP, Reedquist KA (2012). Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by acclerating mRNA decay. Ann Rheum Dis 71:424-31.
2. Grabiec AM and Reedquist KA (2013). The ascent of acetylation in the epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 9:311-8.
3. Angiolilli C, Grabiec AM, Ferguson BS, Ospelt C, Malvar Fernandez B, van Es IE, van Baarsen LGM, Gay S, McKinsey TA, Tak PP, Baeten DL, Reedquist KA (2014). Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression. Ann Rheum Dis doi:10.1136/annrheumdis-2014-205635.
4. Klein K, Grabiec AM, Gay RE, Kolling C, Lin LL, Gay S, Tak PP, Prinjha RK, Ospelt C, Reedquist KA (2014). The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matric degrading enzymes in rheumatoid arthritis synovial fibroblasts. Ann Rheum Dis doi:10.1136/annrheumdis-2014-205809.