SRP108640 PRJNA389321 GSE99702 Cell-type specific epigenetic regulome in Systemic Sclerosis skin Skin systemic sclerosis (Scleroderma, SSc) is an autoimmune disease while its epigenetic regulatory mechanism is not known. We surveyed the genome-wide active regulatory elements in fresh human skin cells, using Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) in longitudinal skin from healthy volunteers and affected and unaffected skin from patients with SSc. We created robust pipelines that enable accurate single molecule counting and allelic discrimination from clinical material in vivo without clonal expansion. We generated high-resolution epigenetic regulomes of 9 cell types in normal and SSc skins, and identified 106044 cell type specific accessible sites. Motif analysis of these peaks predicted known and novel transcription factors regulating each cell type. For each cell type, we discovered thousands of accessible sites are differential in normal versus unaffected and affected skin from patients with SSc. We predicted novel transcription factors regulating SSc in a cell type specific manner, and predicted the relative contributions of each cell type in driving skin SSc. ATAC-seq also revealed novel elements that escape X chromosome inactivation, which coordinately impact genes with immune function. Overall design: In this study, we developed a systematic approach to characterize chromatin dynamics in normal and patients with systemic sclerosis. We examined chromatin structure using ATAC-seq in normal human skin and affected and unaffected skin cells from patients with SSc. We generate and analyze 114 high-resolution personal regulomes of a multiple cell type, CD4+ and CD8+ T cell, pericyte, dendritic, langerhan, endotheliocyte, macrophage, fibroblast and keratinocyte, and comprised over 4.5 billion measurements. Samples were accumulated from 11 normal donors and 8 SSc patients. We develop methods to integrate diverse sources of genomic and epigenomic information to address the regulatory pattern in divergent cells in human skin in vivo. Healthy human donors provided 5 mm punch skin sample and each sample was digested to single cell suspension. Patients' samples were obtained from clinically affected skin of the arm and clinically unaffected skin of the back of patients with SSc. From each skin biopsy, we isolated CD4+ and CD8+ T cells, fibroblasts, melanocytes, macrophages, endothelial and dendritic cells using flow cytometry. For each cell type we then performed ATAC-seq to map the location and accessibility of regulatory elements genome-wide from 50,000 cells. GSE99702 pubmed 33318485 pubmed 33203843