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Título: | Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci |
Autor: | Li, Tianlu; Ortiz-Fernández, Lourdes CSIC ORCID; Andrés-León, Eduardo CSIC ORCID CVN ; Ciudad, Laura CSIC ORCID; Javierre, Biola M.; López-Isac, Elena; Guillén del Castillo, Alfredo; Simeón, Carmen P.; Ballestar, Estéban; Martín, Javier | Palabras clave: | Systemic sclerosis DNA methylation Epigenetics Long-distance regulation Hi-C Genetic susceptibility variants CTCF |
Fecha de publicación: | 2020 | Editor: | BioMed Central | Citación: | Genome Medicine: 12(1): 81 (2020) | Resumen: | [Background]: Systemic sclerosis (SSc) is a genetically complex autoimmune disease mediated by the interplay between genetic and epigenetic factors in a multitude of immune cells, with CD4+ T lymphocytes as one of the principle drivers of pathogenesis. [Methods]: DNA samples exacted from CD4+ T cells of 48 SSc patients and 16 healthy controls were hybridized on MethylationEPIC BeadChip array. In parallel, gene expression was interrogated by hybridizing total RNA on Clariom™ S array. Downstream bioinformatics analyses were performed to identify correlating differentially methylated CpG positions (DMPs) and differentially expressed genes (DEGs), which were then confirmed utilizing previously published promoter capture Hi-C (PCHi-C) data. [Results]: We identified 9112 and 3929 DMPs and DEGs, respectively. These DMPs and DEGs are enriched in functional categories related to inflammation and T cell biology. Furthermore, correlation analysis identified 17,500 possible DMP-DEG interaction pairs within a window of 5 Mb, and utilizing PCHi-C data, we observed that 212 CD4+ T cell-specific pairs of DMP-DEG also formed part of three-dimensional promoter-enhancer networks, potentially involving CTCF. Finally, combining PCHi-C data with SSc GWAS data, we identified four important SSc-associated susceptibility loci, TNIP1 (rs3792783), GSDMB (rs9303277), IL12RB1 (rs2305743), and CSK (rs1378942), that could potentially interact with DMP-DEG pairs cg17239269-ANXA6, cg19458020-CCR7, cg10808810-JUND, and cg11062629-ULK3, respectively. [Conclusion]: Our study unveils a potential link between genetic, epigenetic, and transcriptional deregulation in CD4+ T cells of SSc patients, providing a novel integrated view of molecular components driving SSc pathogenesis. |
Descripción: | © The Author(s). 2020. | Versión del editor: | https://doi.org/10.1186/s13073-020-00779-6 | URI: | http://hdl.handle.net/10261/220381 | DOI: | 10.1186/s13073-020-00779-6 | E-ISSN: | 1756-994X |
Aparece en las colecciones: | (IPBLN) Artículos |
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