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

Ainsworth, R. I. et al. (2022) Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function. Nature Communications, 13, 6221. (doi: 10.1038/s41467-022-33785-w) (PMID:36266270) (PMCID:PMC9584907)

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.

• Item Type: Articles
• Additional Information: Funding of this work was provided, in part, by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01AR065466 (W.W. and G.S.F.) and R01AR071321 (G.S.F.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ansalone, Dr Cecilia
• Authors: Ainsworth, R. I., Hammaker, D., Nygaard, G., Ansalone, C., Machado, C., Zhang, K., Zheng, L., Carrillo, L., Wildberg, A., Kuhs, A., Svensson, M. N. D., Boyle, D. L., Firestein, G. S., and Wang, W.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature Communications 13: 6221
• Publisher Policy: Reproduced under a Creative Commons License
• Data DOI: 10.6084/m9.figshare.c.6152160