Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function

Richard I. Ainsworth, Deepa Hammaker, Gyrid Nygaard, Cecilia Ansalone, Camilla Machado, Kai Zhang, Lina Zheng, Lucy Carrillo, Andre Wildberg, Amanda Kuhs, Mattias N. D. Svensson, David L. Boyle, Gary S. Firestein () and Wei Wang ()
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Richard I. Ainsworth: University of California, San Diego
Deepa Hammaker: University of California, San Diego
Gyrid Nygaard: University of California, San Diego
Cecilia Ansalone: University of California, San Diego
Camilla Machado: University of California, San Diego
Kai Zhang: University of California, San Diego
Lina Zheng: University of California, San Diego
Lucy Carrillo: University of California, San Diego
Andre Wildberg: University of California, San Diego
Amanda Kuhs: University of California, San Diego
Mattias N. D. Svensson: University of California, San Diego
David L. Boyle: University of California, San Diego
Gary S. Firestein: University of California, San Diego
Wei Wang: University of California, San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease. To tackle this challenge, we develop and apply a systems biology approach to identify important transcription factors (TFs) in individual RA fibroblast-like synoviocyte (FLS) cell lines by integrating transcriptomic and epigenomic information. Based on the relative importance of the identified TFs, we stratify the RA FLS cell lines into two subtypes with distinct phenotypes and predicted active pathways. We biologically validate these predictions for the top subtype-specific TF RARα and demonstrate differential regulation of TGFβ signaling in the two subtypes. This study characterizes clusters of RA cell lines with distinctive TF biology by integrating transcriptomic and epigenomic data, which could pave the way towards a greater understanding of disease heterogeneity.

Date: 2022
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DOI: 10.1038/s41467-022-33785-w

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