Chromatin Activity at GWAS Loci Identifies T Cell States Driving Complex Immune Diseases

Overview

Journal Nat Genet

Specialty Genetics

Date 2019 Sep 25

PMID 31548716

Citations 55

Authors

Blagoje Soskic

Eddie Cano-Gamez

Deborah J Smyth

Wendy C Rowan

Nikolina Nakic

Jorge Esparza-Gordillo

Lara Bossini-Castillo

David F Tough

Christopher G C Larminie

Paola G Bronson

David Wille

Gosia Trynka

Affiliations

Soon will be listed here.

Abstract

Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while the presence of cytokines fine-tuned the magnitude of changes. We developed a statistical method that accounts for subtle changes in the chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune-disease-associated variants in early rather than late activation of memory CD4 T cells, with modest differences across cytokines. Furthermore, variants associated with inflammatory bowel disease are enriched in type 1 T helper (T1) cells, whereas variants associated with Alzheimer's disease are enriched in different macrophage cell states. Our results represent an in-depth analysis of immune-disease-associated variants across a comprehensive panel of activation states of T cells and macrophages.

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References

Chen L, Ge B, Casale F, Vasquez L, Kwan T, Garrido-Martin D . Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells. Cell. 2016; 167(5):1398-1414.e24. PMC: 5119954. DOI: 10.1016/j.cell.2016.10.026. View

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

Senecal V, Deblois G, Beauseigle D, Schneider R, Brandenburg J, Newcombe J . Production of IL-27 in multiple sclerosis lesions by astrocytes and myeloid cells: Modulation of local immune responses. Glia. 2015; 64(4):553-69. DOI: 10.1002/glia.22948. View

Ferreira M, Vonk J, Baurecht H, Marenholz I, Tian C, Hoffman J . Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat Genet. 2017; 49(12):1752-1757. PMC: 5989923. DOI: 10.1038/ng.3985. View

Maurano M, Humbert R, Rynes E, Thurman R, Haugen E, Wang H . Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012; 337(6099):1190-5. PMC: 3771521. DOI: 10.1126/science.1222794. View

Tsoi L, Stuart P, Tian C, Gudjonsson J, Das S, Zawistowski M . Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants. Nat Commun. 2017; 8:15382. PMC: 5458077. DOI: 10.1038/ncomms15382. View

Jostins L, Ripke S, Weersma R, Duerr R, McGovern D, Hui K . Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491(7422):119-24. PMC: 3491803. DOI: 10.1038/nature11582. View

Calderon D, Nguyen M, Mezger A, Kathiria A, Muller F, Nguyen V . Landscape of stimulation-responsive chromatin across diverse human immune cells. Nat Genet. 2019; 51(10):1494-1505. PMC: 6858557. DOI: 10.1038/s41588-019-0505-9. View

Tivol E, Borriello F, Schweitzer A, Lynch W, Bluestone J, Sharpe A . Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3(5):541-7. DOI: 10.1016/1074-7613(95)90125-6. View

10.

McInnes I, Buckley C, Isaacs J . Cytokines in rheumatoid arthritis - shaping the immunological landscape. Nat Rev Rheumatol. 2015; 12(1):63-8. DOI: 10.1038/nrrheum.2015.171. View

11.

Schubert D, Bode C, Kenefeck R, Hou T, Wing J, Kennedy A . Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014; 20(12):1410-1416. PMC: 4668597. DOI: 10.1038/nm.3746. View

12.

Li H, Durbin R . Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010; 26(5):589-95. PMC: 2828108. DOI: 10.1093/bioinformatics/btp698. View

13.

Beecham A, Patsopoulos N, Xifara D, Davis M, Kemppinen A, Cotsapas C . Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013; 45(11):1353-60. PMC: 3832895. DOI: 10.1038/ng.2770. View

14.

Minoux M, Holwerda S, Vitobello A, Kitazawa T, Kohler H, Stadler M . Gene bivalency at Polycomb domains regulates cranial neural crest positional identity. Science. 2017; 355(6332). DOI: 10.1126/science.aal2913. View

15.

Martinez F, Gordon S . The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. PMC: 3944738. DOI: 10.12703/P6-13. View

16.

Babaloo Z, Yeganeh R, Farhoodi M, Baradaran B, Bonyadi M, Aghebati L . Increased IL-17A but decreased IL-27 serum levels in patients with multiple sclerosis. Iran J Immunol. 2013; 10(1):47-54. DOI: IJIv10i1A6. View

17.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

18.

Jiang H, Lei R, Ding S, Zhu S . Skewer: a fast and accurate adapter trimmer for next-generation sequencing paired-end reads. BMC Bioinformatics. 2014; 15:182. PMC: 4074385. DOI: 10.1186/1471-2105-15-182. View

19.

Onengut-Gumuscu S, Chen W, Burren O, Cooper N, Quinlan A, Mychaleckyj J . Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet. 2015; 47(4):381-6. PMC: 4380767. DOI: 10.1038/ng.3245. View

20.

Demenais F, Margaritte-Jeannin P, Barnes K, Cookson W, Altmuller J, Ang W . Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. Nat Genet. 2017; 50(1):42-53. PMC: 5901974. DOI: 10.1038/s41588-017-0014-7. View