دورية أكاديمية
Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation.
العنوان: | Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation. |
---|---|
المؤلفون: | Chandra A; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Yoon S; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Michieletto MF; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA., Goldman N; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Ferrari EK; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Abedi M; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Johnson I; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Fasolino M; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Pham K; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Joannas L; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA., Kee BL; Department of Pathology, Committees on Cancer Biology and Immunology, University of Chicago, Chicago, IL 60637, USA., Henao-Mejia J; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jhena@pennmedicine.upenn.edu., Vahedi G; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: vahedi@pennmedicine.upenn.edu. |
المصدر: | Immunity [Immunity] 2023 Jul 11; Vol. 56 (7), pp. 1451-1467.e12. Date of Electronic Publication: 2023 May 31. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 9432918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4180 (Electronic) Linking ISSN: 10747613 NLM ISO Abbreviation: Immunity Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Cambridge, MA : Cell Press Original Publication: Cambridge, Mass. : Cell Press, c1994- |
مواضيع طبية MeSH: | T-Lymphocytes* , Hypersensitivity*/genetics, Humans ; Mice ; Animals ; Cell Differentiation/genetics ; Hematopoiesis ; Inflammation/genetics ; Regulatory Sequences, Nucleic Acid ; Enhancer Elements, Genetic/genetics |
مستخلص: | Multi-enhancer hubs are spatial clusters of enhancers present across numerous developmental programs. Here, we studied the functional relevance of these three-dimensional structures in T cell biology. Mathematical modeling identified a highly connected multi-enhancer hub at the Ets1 locus, comprising a noncoding regulatory element that was a hotspot for sequence variation associated with allergic disease in humans. Deletion of this regulatory element in mice revealed that the multi-enhancer connectivity was dispensable for T cell development but required for CD4 + T helper 1 (Th1) differentiation. These mice were protected from Th1-mediated colitis but exhibited overt allergic responses. Mechanistically, the multi-enhancer hub controlled the dosage of Ets1 that was required for CTCF recruitment and assembly of Th1-specific genome topology. Our findings establish a paradigm wherein multi-enhancer hubs control cellular competence to respond to an inductive cue through quantitative control of gene dosage and provide insight into how sequence variation within noncoding elements at the Ets1 locus predisposes individuals to allergic responses. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 Elsevier Inc. All rights reserved.) |
References: | Cell Rep. 2019 Oct 29;29(5):1203-1220.e7. (PMID: 31665634) Nat Immunol. 2022 Jul;23(7):1052-1062. (PMID: 35726060) Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):E2183-E2192. (PMID: 29463736) J Immunol. 2000 Mar 15;164(6):2857-60. (PMID: 10706669) Bioinformatics. 2015 Oct 1;31(19):3092-8. (PMID: 26034063) Cell. 2013 Apr 11;153(2):307-19. (PMID: 23582322) Nucleic Acids Res. 2022 Jul 5;50(W1):W175-W182. (PMID: 35325188) Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943) Genome Biol. 2015 Dec 01;16:259. (PMID: 26619908) Proc Natl Acad Sci U S A. 1990 May;87(10):3723-7. (PMID: 2187191) Nature. 2015 Apr 23;520(7548):558-62. (PMID: 25686607) Bioinformatics. 2009 Jul 15;25(14):1754-60. (PMID: 19451168) Science. 2009 Oct 9;326(5950):289-93. (PMID: 19815776) Nat Genet. 2020 Nov;52(11):1227-1238. (PMID: 33020665) Nat Methods. 2021 Nov;18(11):1333-1341. (PMID: 34725479) Nat Genet. 2015 Dec;47(12):1449-1456. (PMID: 26482879) Immunity. 1998 Nov;9(5):745-55. (PMID: 9846495) PLoS Comput Biol. 2013;9(8):e1003118. (PMID: 23950696) Nature. 1995 Oct 19;377(6550):639-42. (PMID: 7566177) Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7588-92. (PMID: 7689222) Elife. 2017 Jan 16;6:. (PMID: 28079019) Int Immunol. 1993 Nov;5(11):1461-71. (PMID: 7903159) Cell. 2018 May 17;173(5):1165-1178.e20. (PMID: 29706548) Science. 2010 Jul 2;329(5987):89-93. (PMID: 20595614) Nature. 2019 Apr;568(7750):49-54. (PMID: 30886393) Genome Biol. 2020 Sep 30;21(1):256. (PMID: 32998764) Annu Rev Biochem. 2011;80:437-71. (PMID: 21548782) Cell. 2014 Dec 18;159(7):1665-80. (PMID: 25497547) Elife. 2017 Sep 21;6:. (PMID: 28933695) Cell. 2021 Mar 4;184(5):1262-1280.e22. (PMID: 33636129) Nucleic Acids Res. 2016 Oct 14;44(18):8714-8725. (PMID: 27439714) Cell. 2017 Sep 21;171(1):103-119.e18. (PMID: 28938112) J Exp Med. 2016 May 2;213(5):687-96. (PMID: 27069114) Nat Methods. 2016 Nov;13(11):919-922. (PMID: 27643841) Nature. 2017 Mar 23;543(7646):519-524. (PMID: 28273065) Genome Biol. 2014;15(12):550. (PMID: 25516281) EMBO J. 2010 Jul 7;29(13):2147-60. (PMID: 20517297) Nat Methods. 2008 Oct;5(10):877-9. (PMID: 18806792) Mol Cancer. 2003 Aug 20;2:29. (PMID: 12971829) Cell. 2018 Jun 14;173(7):1796-1809.e17. (PMID: 29779944) Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21301-6. (PMID: 23236188) Immunity. 2020 Feb 18;52(2):257-274.e11. (PMID: 32049053) Elife. 2019 Jul 11;8:. (PMID: 31294690) Genes Dev. 1992 Jun;6(6):975-90. (PMID: 1592264) Science. 2010 Feb 26;327(5969):1098-102. (PMID: 20185720) Oncogene. 1994 Jun;9(6):1551-65. (PMID: 8183549) Cell. 2021 Jun 24;184(13):3573-3587.e29. (PMID: 34062119) PLoS Biol. 2007 Dec;5(12):e325. (PMID: 18076286) Genetics. 2017 Sep;207(1):139-151. (PMID: 28679547) Nat Genet. 2013 Aug;45(8):907-11. (PMID: 23817569) Nat Commun. 2022 Mar 24;13(1):1602. (PMID: 35332165) Cell Res. 2016 Dec;26(12):1345-1348. (PMID: 27886167) Annu Rev Immunol. 2012;30:707-31. (PMID: 22224760) J Immunol. 2017 Aug 1;199(3):1131-1141. (PMID: 28637900) Genome Biol. 2008;9(9):R137. (PMID: 18798982) Mol Cell. 2017 Sep 21;67(6):1037-1048.e6. (PMID: 28890333) Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) Nature. 2015 Jul 9;523(7559):240-4. (PMID: 26030525) Mol Cell. 2010 May 28;38(4):576-89. (PMID: 20513432) Clin Diabetes Endocrinol. 2020 Nov 04;6(1):20. (PMID: 33292863) Nature. 2022 May;605(7911):754-760. (PMID: 35508662) Nat Immunol. 2020 Jul;21(7):700-703. (PMID: 32577013) Nat Commun. 2015 May 12;6:7147. (PMID: 25962338) Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) Curr Opin Genet Dev. 2021 Apr;67:5-9. (PMID: 33202367) Nat Biotechnol. 2011 Jan;29(1):24-6. (PMID: 21221095) J Exp Med. 2017 Jun 5;214(6):1581-1592. (PMID: 28484078) Nucleic Acids Res. 2014 Jul;42(Web Server issue):W187-91. (PMID: 24799436) Bioinformatics. 2020 May 1;36(10):2980-2985. (PMID: 32003791) Immunity. 2006 Aug;25(2):225-36. (PMID: 16919487) JCI Insight. 2019 Mar 7;4(5):. (PMID: 30843878) Cold Spring Harb Protoc. 2016 Feb 01;2016(2):pdb.prot090704. (PMID: 26832688) Hum Mol Genet. 2006 Apr 15;15 Spec No 1:R67-74. (PMID: 16651371) Immunity. 2012 Jun 29;36(6):921-32. (PMID: 22608498) Nat Genet. 2018 Aug;50(8):1151-1160. (PMID: 29988121) Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313) Nat Methods. 2012 Jul;9(7):671-5. (PMID: 22930834) Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278) Mol Cell. 2019 Mar 21;73(6):1174-1190.e12. (PMID: 30745086) Nat Commun. 2012;3:1268. (PMID: 23232398) Immunity. 2018 Dec 18;49(6):1034-1048.e8. (PMID: 30566881) |
معلومات مُعتمدة: | U01 DK112217 United States DK NIDDK NIH HHS; U01 DA052715 United States DA NIDA NIH HHS; R01 HL145754 United States HL NHLBI NIH HHS; U01 DK127768 United States DK NIDDK NIH HHS; R01 HL136572 United States HL NHLBI NIH HHS; R01 AI106352 United States AI NIAID NIH HHS; UC4 DK112217 United States DK NIDDK NIH HHS; R01 AI168240 United States AI NIAID NIH HHS; R01 AI168136 United States AI NIAID NIH HHS |
فهرسة مساهمة: | Keywords: 3D genome organization; CD4 T helper differentiation; ETS1; allergic inflammation; allergy; asthma; colitis; dosage control; multi-enhancer hubs; transcription factor |
تواريخ الأحداث: | Date Created: 20230601 Date Completed: 20230714 Latest Revision: 20240508 |
رمز التحديث: | 20240508 |
مُعرف محوري في PubMed: | PMC10979463 |
DOI: | 10.1016/j.immuni.2023.05.004 |
PMID: | 37263273 |
قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!