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The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis

2024; Nature Portfolio; Volume: 15; Issue: 1 Linguagem: Inglês

10.1038/s41467-024-48620-7

2041-1723

Kathryn Weinand, Saori Sakaue, Aparna Nathan, A. Helena Jonsson, Fan Zhang, Gerald F. Watts, Majd Al Suqri, Zhu Zhu, Jennifer S. Albrecht, William Apruzzese, Nirmal K. Banda, Jennifer L. Barnas, Joan M. Bathon, Ami Ben‐Artzi, Brendan F. Boyce, David L. Boyle, S. Louis Bridges, Vivian P. Bykerk, Debbie Campbell, Hayley L. Carr, Arnold Ceponis, Adam Chicoine, Andrew Cordle, Michelle Curtis, Kevin D. Deane, Edward F. DiCarlo, Patrick Dunn, Andrew Filer, Gary S. Firestein, Lindsy Forbess, Laura Geraldino‐Pardilla, Susan M. Goodman, Ellen M. Gravallese, Peter K. Gregersen, Joel M. Guthridge, María Gutiérrez‐Arcelus, Siddarth Gurajala, V. Michael Holers, Diane Horowitz, Laura B. Hughes, Kazuyoshi Ishigaki, Lionel B. Ivashkiv, Judith A. James, Joyce B. Kang, Gregory Keras, Ilya Korsunsky, Amit Lakhanpal, James A. Lederer, Zhihan J. Li, Yuhong Li, Katherine P. Liao, Arthur M. Mandelin, Ian Mantel, Mark Maybury, Andrew McDavid, Joseph Mears, Nida Meednu, Nghia Millard, Larry W. Moreland, Alessandra Nerviani, Dana E. Orange, Harris Perlman, Costantino Pitzalis, Javier Rangel‐Moreno, Karim Raza, Yakir Reshef, Christopher T. Ritchlin, Felice Rivellese, William H. Robinson, Laurie Rumker, Ilfita Sahbudin, Dagmar Scheel‐Toellner, Jennifer Seifert, Kamil Slowikowski, Melanie H. Smith, Darren Tabechian, Paul J. Utz, Dana Weisenfeld, Michael H. Weisman, Qian Xiao, Deepak A. Rao, Jennifer H. Anolik, Michael B. Brenner, Laura T. Donlin, Kevin Wei, Soumya Raychaudhuri,

Chronic Lymphocytic Leukemia Research

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.