RT Journal Article
SR Electronic
T1 A novel network approach reveals tissue-specific cellular modulators of the immune-fibrotic axis in systemic sclerosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 038950
DO 10.1101/038950
A1 Jaclyn N. Taroni
A1 J. Matthew Mahoney
A1 Casey S. Greene
A1 Viktor Martyanov
A1 Tammara A. Wood
A1 Romy B. Christmann
A1 Harrison W. Farber
A1 Robert A. Lafyatis
A1 Christopher P. Denton
A1 Monique E. Hinchcliff
A1 Patricia A. Pioli
A1 Michael L. Whitfield
YR 2016
UL http://biorxiv.org/content/early/2016/02/06/038950.abstract
AB Systems biology uses genome-scale data to determine the molecular mechanisms behind normal and disease states. We developed a novel computational method, which allowed for the first time, identification of a disease-associated signature across multiple tissues and organs in systemic sclerosis (SSc), a rare and sometimes fatal autoimmune disease. We find a common immune-fibrotic axis associated with the most severe disease phenotypes, including pulmonary fibrosis and pulmonary arterial hypertension. We evaluated disease-associated gene-gene interactions in the context of tissue-specific functional genomic networks and utilized differential network analysis to gain important insights into the role of pro-fibrotic macrophages in SSc. Using a novel cell type-aware multi-network approach, we find that genes modulated by immunosuppressive treatment occupy privileged positions in the skin-specific network. In total, this study not only presents a set of putative therapeutic targets for SSc, but a framework for multi-tissue functional genomic studies of complex human disease.