دورية أكاديمية
أعرض في EDS

Resolving mechanisms of immune-mediated disease in primary CD4 T cells.

التفاصيل البيبلوغرافية
العنوان: Resolving mechanisms of immune-mediated disease in primary CD4 T cells.
المؤلفون: Bourges C; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK., Groff AF; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Burren OS; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK., Gerhardinger C; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Mattioli K; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Hutchinson A; MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK., Hu T; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK., Anand T; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK., Epping MW; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK., Wallace C; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Smith KG; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK., Rinn JL; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.; Department of Biochemistry, BioFrontiers Institute, University of Colorado, Boulder, CO, USA., Lee JC; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
المصدر: EMBO molecular medicine [EMBO Mol Med] 2020 May 08; Vol. 12 (5), pp. e12112. Date of Electronic Publication: 2020 Apr 01.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101487380 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1757-4684 (Electronic) Linking ISSN: 17574676 NLM ISO Abbreviation: EMBO Mol Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Chichester, West Sussex : Wiley-Blackwell
مواضيع طبية MeSH: CD4-Positive T-Lymphocytes* , NF-kappa B*, Autoimmunity ; Humans ; Polymorphism, Single Nucleotide
مستخلص: Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune-mediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-κB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-κB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.
(© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
References: Nat Genet. 2012 Dec;44(12):1336-40. (PMID: 23143596)
Genome Biol. 2011 Jul 29;12(7):R70. (PMID: 21801342)
Nat Genet. 2012 May 06;44(6):676-80. (PMID: 22561518)
Nat Commun. 2018 Dec 19;9(1):5380. (PMID: 30568279)
Genome Res. 2004 Jun;14(6):1188-90. (PMID: 15173120)
PLoS One. 2009;4(5):e5430. (PMID: 19412549)
Nat Biotechnol. 2015 Sep;33(9):985-989. (PMID: 26121415)
Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943)
Genome Biol. 2016 Nov 1;17(1):212. (PMID: 27799070)
Nature. 2017 Jul 13;547(7662):173-178. (PMID: 28658209)
Cell. 2016 Jun 2;165(6):1530-1545. (PMID: 27259154)
Cell. 2018 Nov 29;175(6):1701-1715.e16. (PMID: 30449622)
Gut. 2019 Aug;68(8):1386-1395. (PMID: 31030191)
Nature. 2012 Nov 1;491(7422):119-24. (PMID: 23128233)
Am J Hum Genet. 2017 Jul 6;101(1):5-22. (PMID: 28686856)
Nat Genet. 2019 Oct;51(10):1494-1505. (PMID: 31570894)
Nat Genet. 2012 Dec;44(12):1341-8. (PMID: 23143594)
J Clin Invest. 2011 Oct;121(10):4170-9. (PMID: 21946256)
PLoS Genet. 2016 Mar 25;12(3):e1005908. (PMID: 27015630)
Nat Genet. 2015 Sep;47(9):979-986. (PMID: 26192919)
Nat Protoc. 2012 Sep;7(9):1728-40. (PMID: 22936215)
Cell Syst. 2016 Nov 23;3(5):491-495.e5. (PMID: 27863955)
Nat Biotechnol. 2016 Feb;34(2):184-191. (PMID: 26780180)
Nat Genet. 2013 Nov;45(11):1353-60. (PMID: 24076602)
J Exp Med. 2018 Mar 05;215(3):985-997. (PMID: 29436394)
J Immunol Methods. 2014 Jun;408:123-31. (PMID: 24910411)
CRISPR J. 2022 Feb;5(1):123-130. (PMID: 35119294)
Nat Genet. 2015 Apr;47(4):381-6. (PMID: 25751624)
Nat Commun. 2017 Jul 17;8:16021. (PMID: 28714469)
Cell. 2013 Nov 7;155(4):934-47. (PMID: 24119843)
Genes Immun. 2019 Feb;20(2):103-111. (PMID: 29483615)
J Clin Invest. 2015 Jun;125(6):2250-60. (PMID: 25985270)
Nat Genet. 2011 Nov 06;43(12):1193-201. (PMID: 22057235)
Nat Genet. 2013 Jul;45(7):730-8. (PMID: 23749187)
Hum Mutat. 2019 Sep;40(9):1292-1298. (PMID: 31228310)
Nat Biotechnol. 2012 Feb 26;30(3):271-7. (PMID: 22371084)
Cell. 2016 Nov 17;167(5):1369-1384.e19. (PMID: 27863249)
Genet Epidemiol. 2009 Jan;33(1):79-86. (PMID: 18642345)
EMBO Mol Med. 2020 May 8;12(5):e12112. (PMID: 32239644)
Nat Protoc. 2011 Nov 03;6(12):1860-9. (PMID: 22051799)
Cell. 2013 Apr 11;153(2):307-19. (PMID: 23582322)
Nat Genet. 2013 Jun;45(6):670-5. (PMID: 23603763)
Nature. 2020 Jan;577(7789):179-189. (PMID: 31915397)
Proc Natl Acad Sci U S A. 2016 May 10;113(19):5364-9. (PMID: 27078102)
Hum Mol Genet. 2012 Dec 1;21(23):5202-8. (PMID: 22922229)
PLoS One. 2013;8(3):e60298. (PMID: 23555950)
Trends Immunol. 2001 Sep;22(9):490-6. (PMID: 11525939)
Cell. 2016 Jun 2;165(6):1519-1529. (PMID: 27259153)
Nat Genet. 2011 Mar;43(3):253-8. (PMID: 21336280)
Nat Methods. 2015 Oct;12(10):931-4. (PMID: 26301843)
Science. 2000 Sep 29;289(5488):2350-4. (PMID: 11009421)
Nature. 2015 Feb 19;518(7539):337-43. (PMID: 25363779)
Nat Biotechnol. 2016 Nov;34(11):1180-1190. (PMID: 27701403)
Genome Res. 2012 Sep;22(9):1748-59. (PMID: 22955986)
Cell. 1997 Oct 17;91(2):243-52. (PMID: 9346241)
Mol Cell. 2014 Oct 23;56(2):219-231. (PMID: 25263595)
Am J Hum Genet. 2017 Jul 6;101(1):75-86. (PMID: 28686857)
Bioinformatics. 2018 Mar 1;34(5):787-794. (PMID: 29028988)
PLoS Genet. 2014 Sep 04;10(9):e1004610. (PMID: 25188404)
PLoS Comput Biol. 2020 Apr 13;16(4):e1007829. (PMID: 32282791)
Cell. 2013 Sep 12;154(6):1380-9. (PMID: 23992846)
معلومات مُعتمدة: MC UU 00002/4 International UK Research and Innovation | Medical Research Council (MRC); 105920/Z/14/Z International Wellcome Trust (WT); M2018/3 International Crohn's and Colitis UK (Crohn's & Colitis UK); International National Institutes of Health Oxford-Cambridge Scholars Program; WT107881 International Wellcome Trust (WT); International Howard Hughes Medical Institute (HHMI); International National Institute for Health Research; International GlaxoSmithKline; EP/R511870/1 International UK Research and Innovation | Engineering and Physical Sciences Research Council (EPSRC); United Kingdom Wellcome Trust; MC_UU_00002/4 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Keywords: GWAS; MPRA; CD4 T cells; TNFAIP3; super-enhancer
سلسلة جزيئية: GEO GSE135925; GSE136092
المشرفين على المادة: 0 (NF-kappa B)
تواريخ الأحداث: Date Created: 20200403 Date Completed: 20210818 Latest Revision: 20240328
رمز التحديث: 20240329
مُعرف محوري في PubMed: PMC7207160
DOI: 10.15252/emmm.202012112
PMID: 32239644
قاعدة البيانات: MEDLINE
الوصف
تدمد:1757-4684
DOI:10.15252/emmm.202012112