The epigenetic architecture at gene promoters
The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance.
Klein K, Frank-Bertoncelj M, Karouzakis E, Gay RE, Kolling C, Ciurea A, Bostanci N, Belibasakis GN, Lin LL, Distler O, Gay S and Ospelt C.
Synovial fibroblasts drive inflammation and joint destruction in chronic arthritis. In this study, we show that synovial fibroblasts possess a distinct type of LPS tolerance compared to macrophages and other types of fibroblasts. In synovial and dermal fibroblasts, genes that were non-tolerizable after repeated LPS stimulation included pro-inflammatory cytokines, chemokines and matrix metalloproteinases, whereas anti-viral genes were tolerizable. In macrophages, all measured genes were tolerizable, whereas in gingival and foreskin fibroblasts these genes were non-tolerizable. Repeated stimulation of synovial fibroblasts with LPS resulted in loss of activating histone marks only in promoters of tolerizable genes. The epigenetic landscape at promoters of tolerizable genes was similar in unstimulated synovial fibroblasts and monocytes, whereas the basal configuration of histone marks profoundly differed in genes that were non-tolerizable in synovial fibroblasts only. Our data suggest that the epigenetic configuration at gene promoters regulates cell-specific LPS-induced responses and primes synovial fibroblasts to sustain their inflammatory response in chronic arthritis.
Our data highlight the importance of the chromatin structure in regulating inflammatory processes in macrophages and different types of fibroblasts. This primes synovial fibroblasts for an enhanced inflammatory and destructive response during repeated activation of Toll-like receptor 4.
Kerstin Klein is a senoir postdoctoral scientist at the Centre of Experimental Rheumatology, University Hospital Zurich since 2010. Her major scientific interest is the the role of epigenetic mechanisms in rheumatoid arthritis and the potential of epigenetic enzymes as future therapeutic targets.
- Synovial fibroblasts