Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci
Li, Tianlu (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Ortiz-Fernández, Lourdes (Instituto de Parasitología y Biomedicina "López-Neyra")
Andrés-León, Eduardo (Instituto de Parasitología y Biomedicina "López-Neyra")
Ciudad, Laura (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Javierre, B. M. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
López-Isac, E. (Instituto de Parasitología y Biomedicina "López-Neyra")
Guillén-Del-Castillo, A. (Hospital Universitari Vall d'Hebron)
Simeón-Aznar, C. P. (Hospital Universitari Vall d'Hebron)
Ballestar, Esteban (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Martín, Javier (Instituto de Parasitología y Biomedicina "López-Neyra")
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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.
Ajuts:	Ministerio de Ciencia e Innovación SAF2017-88086-R Ministerio de Ciencia e Innovación RT2018-101332-B-I00 Instituto de Salud Carlos III RD16-0012-0013
Nota:	Altres ajuts: We thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	CTCF ; DNA methylation ; Epigenetics ; Genetic susceptibility variants ; Hi-C ; Long-distance regulation ; Systemic sclerosis
Publicat a:	Genome Medicine, Vol. 12 Núm. 1 (25 2020) , p. 81, ISSN 1756-994X

DOI: 10.1186/s13073-020-00779-6
PMID: 32977850

17 p, 3.1 MB

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