Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis

Qian Liu, Lisa C. Zaba, Ansuman T. Satpathy, Michelle Longmire, Wen Zhang, Kun Li, Jeffrey Granja, Chuang Guo, Jun Lin, Rui Li, Karen Tolentino, Gabriela Kania, Oliver Distler, David Fiorentino, Lorinda Chung, Kun Qu () and Howard Y. Chang ()
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Qian Liu: University of Science and Technology of China
Lisa C. Zaba: Stanford University School of Medicine
Ansuman T. Satpathy: Stanford University School of Medicine
Michelle Longmire: Stanford University School of Medicine
Wen Zhang: University of Science and Technology of China
Kun Li: University of Science and Technology of China
Jeffrey Granja: Stanford University School of Medicine
Chuang Guo: University of Science and Technology of China
Jun Lin: University of Science and Technology of China
Rui Li: Stanford University School of Medicine
Karen Tolentino: Stanford University School of Medicine
Gabriela Kania: University Hospital Zurich
Oliver Distler: University Hospital Zurich
David Fiorentino: Stanford University School of Medicine
Lorinda Chung: Stanford University School of Medicine
Kun Qu: University of Science and Technology of China
Howard Y. Chang: Stanford University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Systemic sclerosis (SSc) is a disease at the intersection of autoimmunity and fibrosis. However, the epigenetic regulation and the contributions of diverse cell types to SSc remain unclear. Here we survey, using ATAC-seq, the active DNA regulatory elements of eight types of primary cells in normal skin from healthy controls, as well as clinically affected and unaffected skin from SSc patients. We find that accessible DNA elements in skin-resident dendritic cells (DCs) exhibit the highest enrichment of SSc-associated single-nucleotide polymorphisms (SNPs) and predict the degrees of skin fibrosis in patients. DCs also have the greatest disease-associated changes in chromatin accessibility and the strongest alteration of cell–cell interactions in SSc lesions. Lastly, data from an independent cohort of patients with SSc confirm a significant increase of DCs in lesioned skin. Thus, the DCs epigenome links inherited susceptibility and clinically apparent fibrosis in SSc skin, and can be an important driver of SSc pathogenesis.

Date: 2020
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DOI: 10.1038/s41467-020-19702-z

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