Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions

Mojca Frank-Bertoncelj (), Michelle Trenkmann, Kerstin Klein, Emmanuel Karouzakis, Hubert Rehrauer, Anna Bratus, Christoph Kolling, Maria Armaka, Andrew Filer, Beat A. Michel, Renate E. Gay, Christopher D. Buckley, George Kollias, Steffen Gay and Caroline Ospelt
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Mojca Frank-Bertoncelj: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich
Michelle Trenkmann: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich
Kerstin Klein: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich
Emmanuel Karouzakis: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich
Hubert Rehrauer: Functional Genomics Center Zurich, ETH Zurich and University of Zurich
Anna Bratus: Functional Genomics Center Zurich, ETH Zurich and University of Zurich
Christoph Kolling: Schulthess Clinic, Lengghalde 2
Maria Armaka: Biomedical Sciences Research Center ‘Alexander Fleming’
Andrew Filer: Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital
Beat A. Michel: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich
Renate E. Gay: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich
Christopher D. Buckley: Institute of Inflammation and Ageing (IIA), University of Birmingham, Queen Elizabeth Hospital
George Kollias: Biomedical Sciences Research Center ‘Alexander Fleming’
Steffen Gay: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich
Caroline Ospelt: Center of Experimental Rheumatology, University Hospital Zurich and University of Zurich

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.

Date: 2017
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DOI: 10.1038/ncomms14852

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