The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis

Kathryn Weinand, Saori Sakaue, Aparna Nathan, Anna Helena Jonsson, Fan Zhang, Gerald F. M. Watts, Majd Al Suqri, Zhu Zhu, Deepak A. Rao, Jennifer H. Anolik, Michael B. Brenner, Laura T. Donlin, Kevin Wei and Soumya Raychaudhuri ()
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Kathryn Weinand: Brigham and Women’s Hospital and Harvard Medical School
Saori Sakaue: Brigham and Women’s Hospital and Harvard Medical School
Aparna Nathan: Brigham and Women’s Hospital and Harvard Medical School
Anna Helena Jonsson: Brigham and Women’s Hospital and Harvard Medical School
Fan Zhang: Brigham and Women’s Hospital and Harvard Medical School
Gerald F. M. Watts: Brigham and Women’s Hospital and Harvard Medical School
Majd Al Suqri: Brigham and Women’s Hospital and Harvard Medical School
Zhu Zhu: Brigham and Women’s Hospital and Harvard Medical School
Deepak A. Rao: Brigham and Women’s Hospital and Harvard Medical School
Jennifer H. Anolik: University of Rochester Medical Center
Michael B. Brenner: Brigham and Women’s Hospital and Harvard Medical School
Laura T. Donlin: Hospital for Special Surgery
Kevin Wei: Brigham and Women’s Hospital and Harvard Medical School
Soumya Raychaudhuri: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent ‘superstates’ corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.

Date: 2024
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DOI: 10.1038/s41467-024-48620-7

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