Multi-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic loci
Abstract Background Genome-wide association studies (GWAS) have uncovered the genetic basis behind many diseases and conditions. However, most of these genetic loci affect regulatory regions, making the interpretation challenging. Chromatin conformation has a fundamental role in gene regulation and...
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2025-02-01
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| Online Access: | https://doi.org/10.1186/s13059-025-03492-y |
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| author | Chenfu Shi Danyun Zhao Jake Butler Antonios Frantzeskos Stefano Rossi James Ding Carlo Ferrazzano Charlotte Wynn Ryan Malcolm Hum Ellie Richards Muskan Gupta Khadijah Patel Chuan Fu Yap Darren Plant Richard Grencis Paul Martin Antony Adamson Stephen Eyre John Bowes Anne Barton Pauline Ho Magnus Rattray Gisela Orozco |
| author_facet | Chenfu Shi Danyun Zhao Jake Butler Antonios Frantzeskos Stefano Rossi James Ding Carlo Ferrazzano Charlotte Wynn Ryan Malcolm Hum Ellie Richards Muskan Gupta Khadijah Patel Chuan Fu Yap Darren Plant Richard Grencis Paul Martin Antony Adamson Stephen Eyre John Bowes Anne Barton Pauline Ho Magnus Rattray Gisela Orozco |
| author_sort | Chenfu Shi |
| collection | DOAJ |
| description | Abstract Background Genome-wide association studies (GWAS) have uncovered the genetic basis behind many diseases and conditions. However, most of these genetic loci affect regulatory regions, making the interpretation challenging. Chromatin conformation has a fundamental role in gene regulation and is frequently used to associate potential target genes to regulatory regions. However, previous studies mostly used small sample sizes and immortalized cell lines instead of primary cells. Results Here we present the most extensive dataset of chromatin conformation with matching gene expression and chromatin accessibility from primary CD4+ and CD8+ T cells to date, isolated from psoriatic arthritis patients and healthy controls. We generated 108 Hi-C libraries (49 billion reads), 128 RNA-seq libraries and 126 ATAC-seq libraries. These data enhance our understanding of the mechanisms by which GWAS variants impact gene regulation, revealing how genetic variation alters chromatin accessibility and structure in primary cells at an unprecedented scale. We refine the mapping of GWAS loci to implicated regulatory elements, such as CTCF binding sites and other enhancer elements, aiding gene assignment. We uncover BCL2L11 as the probable causal gene within the rheumatoid arthritis (RA) locus rs13396472, despite the GWAS variants’ intronic positioning relative to ACOXL, and we identify mechanisms involving SESN3 dysregulation in the RA locus rs4409785. Conclusions Given these genes’ significant role in T cell development and maturation, our work deepens our comprehension of autoimmune disease pathogenesis, suggesting potential treatment targets. In addition, our dataset provides a valuable resource for the investigation of immune-mediated diseases and gene regulatory mechanisms. |
| format | Article |
| id | doaj-art-c8cda9e5afd34a53b53b17cddf2a630f |
| institution | DOAJ |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj-art-c8cda9e5afd34a53b53b17cddf2a630f2025-08-20T02:48:12ZengBMCGenome Biology1474-760X2025-02-0126112910.1186/s13059-025-03492-yMulti-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic lociChenfu Shi0Danyun Zhao1Jake Butler2Antonios Frantzeskos3Stefano Rossi4James Ding5Carlo Ferrazzano6Charlotte Wynn7Ryan Malcolm Hum8Ellie Richards9Muskan Gupta10Khadijah Patel11Chuan Fu Yap12Darren Plant13Richard Grencis14Paul Martin15Antony Adamson16Stephen Eyre17John Bowes18Anne Barton19Pauline Ho20Magnus Rattray21Gisela Orozco22Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterGenome Editing Unit, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterNIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science CentreCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterAbstract Background Genome-wide association studies (GWAS) have uncovered the genetic basis behind many diseases and conditions. However, most of these genetic loci affect regulatory regions, making the interpretation challenging. Chromatin conformation has a fundamental role in gene regulation and is frequently used to associate potential target genes to regulatory regions. However, previous studies mostly used small sample sizes and immortalized cell lines instead of primary cells. Results Here we present the most extensive dataset of chromatin conformation with matching gene expression and chromatin accessibility from primary CD4+ and CD8+ T cells to date, isolated from psoriatic arthritis patients and healthy controls. We generated 108 Hi-C libraries (49 billion reads), 128 RNA-seq libraries and 126 ATAC-seq libraries. These data enhance our understanding of the mechanisms by which GWAS variants impact gene regulation, revealing how genetic variation alters chromatin accessibility and structure in primary cells at an unprecedented scale. We refine the mapping of GWAS loci to implicated regulatory elements, such as CTCF binding sites and other enhancer elements, aiding gene assignment. We uncover BCL2L11 as the probable causal gene within the rheumatoid arthritis (RA) locus rs13396472, despite the GWAS variants’ intronic positioning relative to ACOXL, and we identify mechanisms involving SESN3 dysregulation in the RA locus rs4409785. Conclusions Given these genes’ significant role in T cell development and maturation, our work deepens our comprehension of autoimmune disease pathogenesis, suggesting potential treatment targets. In addition, our dataset provides a valuable resource for the investigation of immune-mediated diseases and gene regulatory mechanisms.https://doi.org/10.1186/s13059-025-03492-yChromatin conformationHi-CInflammatory diseasesGene regulationGWASQTLs |
| spellingShingle | Chenfu Shi Danyun Zhao Jake Butler Antonios Frantzeskos Stefano Rossi James Ding Carlo Ferrazzano Charlotte Wynn Ryan Malcolm Hum Ellie Richards Muskan Gupta Khadijah Patel Chuan Fu Yap Darren Plant Richard Grencis Paul Martin Antony Adamson Stephen Eyre John Bowes Anne Barton Pauline Ho Magnus Rattray Gisela Orozco Multi-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic loci Genome Biology Chromatin conformation Hi-C Inflammatory diseases Gene regulation GWAS QTLs |
| title | Multi-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic loci |
| title_full | Multi-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic loci |
| title_fullStr | Multi-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic loci |
| title_full_unstemmed | Multi-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic loci |
| title_short | Multi-omics analysis in primary T cells elucidates mechanisms behind disease-associated genetic loci |
| title_sort | multi omics analysis in primary t cells elucidates mechanisms behind disease associated genetic loci |
| topic | Chromatin conformation Hi-C Inflammatory diseases Gene regulation GWAS QTLs |
| url | https://doi.org/10.1186/s13059-025-03492-y |
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