PRE2023-CARACTERIZACION FUNCIONAL DE LAS REGIONES GENETICAS ASOCIADAS A LA ESCLEROSIS SISTEMICA-PID2022-139292OB-I00

Systemic sclerosis or scleroderma (SSc) is an autoimmune disease characterized by dysregulation of the immune system and fibrosis of skin and internal organs. The disease dramatically decreases the quality of life and life expectancy of patients. The pathogenesis of SSc is complex, where genetic factors play a key role on disease presentation and progression. Our group has led at the international level the identification of genetic risk factors for SSc. However, the role of SSc-associated variants at the molecular level is still largely unknown. Most of the SSc-associated genetic signals are located in the non-coding genome, making it difficult to identify the causal variants, to determine the genes affected by them, or the mechanisms or cell types in which they play a biological role. Therefore, new strategies are needed to define and validate the functional effect of SSc-risk variants. In this project, we propose to perform the first study of the global chromatin regulatory landscape of relevant cell types in the pathogenesis of the disease, like monocytes, CD4+ T cells and skin fibroblasts. We will assess genes in open chromatin regions by performing ATAC-seq and predicting transcription factor (TF) binding in SSc patients and controls. Furthermore, histone mark and TF patterns will be evaluated by ChIP-seq to identify differentially regulated genes. In addition, a transcriptome analysis will be performed to validate shifts on gene expression.