Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

Genome Medicine

Biola M. Javierre¹  Esteban Ballestar²  Laura Ciudad²  Tianlu Li²  Lourdes Ortiz-Fernández³  Eduardo Andrés-León³  Elena López-Isac³  Javier Martin³  Carmen Pilar Simeón-Aznar⁴  Alfredo Guillén-Del-Castillo⁴ 

[1] 3D Chromatin Organization, Josep Carreras Research Institute (IJC), 08916, Badalona, Barcelona, Spain;Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916, Badalona, Barcelona, Spain;Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain;Unit of Systemic Autoimmunity Diseases, Department of Internal Medicine, Vall d’Hebron Hospital, Barcelona, Spain;

关键词: Systemic sclerosis;    DNA methylation;    Epigenetics;    Long-distance regulation;    Hi-C;    Genetic susceptibility variants;    CTCF;   

DOI  :  10.1186/s13073-020-00779-6

来源: Springer

【 摘 要 】

BackgroundSystemic 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.MethodsDNA 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.ResultsWe 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.ConclusionOur 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.

【 授权许可】

CC BY