RNA-Seq analysis identifies novel roles for the primary cilia gene SPAG17 and the SOX9 locus non-coding RNAs in systemic sclerosis

Systemic sclerosis ( SSc ) is characterized by immune activation, vasculopathy, and unresolving fibrosis in the skin, lungs, and other organs. We performed RNA-Seq analysis on skin biopsies and peripheral blood mononuclear cells ( PBMCs ) from SSc patients and controls to better understand SSc pathogenesis. We analyzed these data to 1) test for case-control differences, and 2) identify genes whose expression levels correlate with SSc severity as measured by local skin score, modified Rodnan skin score ( MRSS ), forced vital capacity ( FVC ), or diffusion capacity for carbon monoxide ( DLCO ). We found that PBMCs from SSc patients showed a strong type 1 interferon signature. This signal replicated in the skin, with additional signals for increased extracellular matrix ( ECM ) genes, classical complement pathway activation, and the presence of B cells. Notably, we observed a marked decrease in the expression of SPAG17 , a cilia component, in SSc skin. We identified genes that correlated with MRSS, DLCO, and FVC in SSc PBMCs and skin using weighted gene co-expression analysis ( WGCNA ). These genes were largely distinct from the case/control differentially expressed genes. In PBMCs, type 1 interferon signatures negatively correlated with DLCO. In SSc skin, ECM gene expression positively correlated with MRSS. Network analysis of SSc skin genes correlated with clinical features identified the non-coding RNAs SOX9-AS1 and ROCR , both near the SOX9 locus, as highly connected, “hub-like” genes in the network. These results identify non-coding RNAs and SPAG17 as novel factors potentially implicated in SSc pathogenesis. ### Competing Interest Statement The authors have declared no competing interest.