دورية أكاديمية
Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4 + regulatory T cells by regulating IL2RA.
| العنوان: | Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4 + regulatory T cells by regulating IL2RA. |
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| المؤلفون: | Andrabi SBA; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Kalim UU; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Palani S; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland., Khan MM; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Khan MH; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Fagersund J; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Orpana J; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Paulin N; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Batkulwar K; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Junttila S; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Buchacher T; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Grönroos T; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland., Toikka L; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland., Ammunet T; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Sen P; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland., Orešič M; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland.; School of Medical Sciences, Örebro University, Örebro 702 81, Sweden., Kumpulainen V; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland., Tuomisto JEE; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland., Sinha R; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305., Marson A; Gladstone-University of California San Francisco Institute of Genomic Immunology, San Francisco, CA 94158., Rasool O; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland., Elo LL; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland.; Institute of Biomedicine, University of Turku, 20520 Turku, Finland., Lahesmaa R; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520, Turku, Finland.; InFLAMES - Innovation Ecosystem Based on the Immune System Flagship University of Turku and Åbo Akademi University, 20520, Turku, Finland.; Institute of Biomedicine, University of Turku, 20520 Turku, Finland. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jun 04; Vol. 121 (23), pp. e2315363121. Date of Electronic Publication: 2024 May 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | RNA, Long Noncoding*/genetics , RNA, Long Noncoding*/metabolism , T-Lymphocytes, Regulatory*/immunology , T-Lymphocytes, Regulatory*/metabolism , Forkhead Transcription Factors*/genetics , Forkhead Transcription Factors*/metabolism , Interleukin-2 Receptor alpha Subunit*/genetics , Interleukin-2 Receptor alpha Subunit*/metabolism, Humans ; Epigenesis, Genetic ; Gene Expression Regulation ; Cell Differentiation/genetics |
| مستخلص: | Regulatory T cells (Tregs) are central in controlling immune responses, and dysregulation of their function can lead to autoimmune disorders or cancer. Despite extensive studies on Tregs, the basis of epigenetic regulation of human Treg development and function is incompletely understood. Long intergenic noncoding RNAs (lincRNA)s are important for shaping and maintaining the epigenetic landscape in different cell types. In this study, we identified a gene on the chromosome 6p25.3 locus, encoding a lincRNA, that was up-regulated during early differentiation of human Tregs. The lincRNA regulated the expression of interleukin-2 receptor alpha (IL2RA), and we named it the lincRNA regulator of IL2RA (LIRIL2R). Through transcriptomics, epigenomics, and proteomics analysis of LIRIL2R-deficient Tregs, coupled with global profiling of LIRIL2R binding sites using chromatin isolation by RNA purification, followed by sequencing, we identified IL2RA as a target of LIRIL2R. This nuclear lincRNA binds upstream of the IL2RA locus and regulates its epigenetic landscape and transcription. CRISPR-mediated deletion of the LIRIL2R-bound region at the IL2RA locus resulted in reduced IL2RA expression. Notably, LIRIL2R deficiency led to reduced expression of Treg-signature genes (e.g., FOXP3 , CTLA4 , and PDCD1 ), upregulation of genes associated with effector T cells (e.g., SATB1 and GATA3 ), and loss of Treg-mediated suppression. Competing Interests: Competing interests statement:A.M. is a cofounder of Arsenal Biosciences, Function Bio, Spotlight Therapeutics, and Survey Genomics; serves on the boards of directors at Function Bio, Spotlight Therapeutics, and Survey Genomics; is a member of the scientific advisory boards of Arsenal Biosciences, Function Bio, Spotlight Therapeutics, Survey Genomics, NewLimit, Amgen, Tenaya, and Lightcast; owns stock in Arsenal Biosciences, Function Bio, Spotlight Therapeutics, NewLimit, Survey Genomics, Tenaya, and Lightcast; and has received fees from Arsenal Biosciences, Spotlight Therapeutics, NewLimit, Amgen, 23andMe, PACT Pharma, Juno Therapeutics, Tenaya, Survey Genomics, Lightcast, Gilead, Trizell, Vertex, Merck, Genentech, AlphaSights, Rupert Case Management, Bernstein, GLG, ClearView Healthcare Partners, and ALDA. A.M. is an investor in and informal advisor to Offline Ventures and a client of EPIQ. S.B.A.A., U.U.K., S.P., V.K., O.R., and R.L. are inventors in a European patent (Oligonucleotides for Modulating Regulatory T Cell Mediated Immunosuppression, patent number: WO2023242469A1) related to this manuscript. All other authors declare no competing interests. |
| References: | Front Cell Dev Biol. 2022 Jun 20;10:831215. (PMID: 35794862) Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792) Cell. 2008 May 30;133(5):775-87. (PMID: 18510923) Nat Immunol. 2013 Apr;14(4):307-8. (PMID: 23507634) Oncotarget. 2016 Mar 22;7(12):13416-28. (PMID: 26967054) Nat Commun. 2019 Apr 29;10(1):1930. (PMID: 31036827) Nat Immunol. 2016 Nov;17(11):1322-1333. (PMID: 27595233) J Vis Exp. 2012 Mar 25;(61):. (PMID: 22472705) J Autoimmun. 2019 Dec;105:102300. (PMID: 31296356) Nat Immunol. 2011 Aug 14;12(9):898-907. (PMID: 21841785) Arthritis Rheum. 2009 Jan;60(1):123-32. (PMID: 19116935) Cell. 2018 Nov 29;175(6):1701-1715.e16. (PMID: 30449622) Immunity. 2019 Feb 19;50(2):362-377.e6. (PMID: 30709738) J Proteome Res. 2018 Sep 7;17(9):2917-2924. (PMID: 30114372) Mucosal Immunol. 2016 Mar;9(2):444-57. (PMID: 26307665) iScience. 2020 Mar 27;23(3):100947. (PMID: 32171124) Nat Immunol. 2015 Mar;16(3):318-325. (PMID: 25621826) Nat Immunol. 2013 Mar;14(3):230-7. (PMID: 23334790) Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11667-72. (PMID: 19571010) J Exp Med. 2023 Mar 6;220(3):. (PMID: 36598533) Cell Rep. 2021 Nov 9;37(6):109973. (PMID: 34758307) Nat Methods. 2017 Jul;14(7):687-690. (PMID: 28581496) Int J Mol Sci. 2022 May 20;23(10):. (PMID: 35628549) Biomed Pharmacother. 2019 Mar;111:386-394. (PMID: 30594051) J Immunol. 2023 Apr 1;210(7):880-887. (PMID: 36947819) Cell Biosci. 2019 Oct 15;9:84. (PMID: 31636893) Front Immunol. 2019 Feb 04;10:115. (PMID: 30778354) PLoS Comput Biol. 2012;8(5):e1002518. (PMID: 22615553) Immunity. 2020 Jun 16;52(6):1119-1132.e4. (PMID: 32362325) J Immunol. 2010 Jul 15;185(2):1071-81. (PMID: 20554955) Nat Biotechnol. 2016 May;34(5):525-7. (PMID: 27043002) Front Immunol. 2019 Dec 03;10:2839. (PMID: 31849995) Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):E3472-E3480. (PMID: 28396406) Front Immunol. 2022 Jun 15;13:856762. (PMID: 35784351) Immunol Rev. 2013 May;253(1):82-96. (PMID: 23550640) Proc Natl Acad Sci U S A. 2021 Jul 27;118(30):. (PMID: 34301886) Eur J Immunol. 2008 Jul;38(7):1814-21. (PMID: 18546144) Immunity. 2012 Nov 16;37(5):785-99. (PMID: 23123060) Front Immunol. 2018 Oct 29;9:2512. (PMID: 30420860) Cell. 2007 Jun 29;129(7):1311-23. (PMID: 17604720) Gigascience. 2021 Feb 16;10(2):. (PMID: 33590861) Proc Natl Acad Sci U S A. 2024 Jun 4;121(23):e2315363121. (PMID: 38805281) Science. 2008 Oct 10;322(5899):271-5. (PMID: 18845758) J Biomed Sci. 2013 Dec 01;20:87. (PMID: 24289115) Eur J Immunol. 2008 Apr;38(4):915-7. (PMID: 18395859) J Cell Physiol. 2019 Dec;234(12):22477-22484. (PMID: 31119756) Blood. 2010 Sep 2;116(9):1443-53. (PMID: 20522714) Nat Commun. 2019 Mar 4;10(1):1037. (PMID: 30833563) Mucosal Immunol. 2015 Jan;8(1):80-93. (PMID: 24917457) Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) Nat Methods. 2012 Mar 04;9(4):357-9. (PMID: 22388286) Nature. 2017 Sep 7;549(7670):111-115. (PMID: 28854172) Cell. 2019 Feb 7;176(4):882-896.e18. (PMID: 30639098) Immunity. 2011 Jul 22;35(1):109-22. (PMID: 21723159) Cell Rep. 2018 Feb 20;22(8):2094-2106. (PMID: 29466736) PLoS Comput Biol. 2018 Oct 18;14(10):e1006541. (PMID: 30335785) Immunol Lett. 2023 Nov;263:123-132. (PMID: 37838026) Front Immunol. 2018 Oct 17;9:2374. (PMID: 30386337) J Immunol. 2012 Sep 1;189(5):2084-8. (PMID: 22851706) Curr Opin Immunol. 2014 Apr;27:1-7. (PMID: 24413387) Nature. 2018 Jul;559(7714):405-409. (PMID: 29995861) Front Immunol. 2018 Sep 25;9:1989. (PMID: 30319599) J Exp Med. 2005 Apr 4;201(7):1061-7. (PMID: 15809351) Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):609-618. (PMID: 30587582) Nucleic Acids Res. 2022 Jan 7;50(D1):D543-D552. (PMID: 34723319) Immunity. 2010 May 28;32(5):605-15. (PMID: 20493732) Nature. 2011 Aug 28;477(7364):295-300. (PMID: 21874018) |
| معلومات مُعتمدة: | 292335 294337 292482 319280 329277 331793 335435 250114 310561 314443 329278 335434 335611 Research Council of Finland (AKA); 677943 955321 EC | ERC | HORIZON EUROPE European Research Council (ERC); NNF19OC0057218 Novo Nordisk Fonden (NNF) |
| فهرسة مساهمة: | Keywords: FOXP3; IL2RA; LIRIL2R; long noncoding RNA; regulatory T cells |
| المشرفين على المادة: | 0 (RNA, Long Noncoding) 0 (Forkhead Transcription Factors) 0 (IL2RA protein, human) 0 (Interleukin-2 Receptor alpha Subunit) 0 (FOXP3 protein, human) |
| تواريخ الأحداث: | Date Created: 20240528 Date Completed: 20240528 Latest Revision: 20240612 |
| رمز التحديث: | 20240612 |
| مُعرف محوري في PubMed: | PMC11161746 |
| DOI: | 10.1073/pnas.2315363121 |
| PMID: | 38805281 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
|---|---|
| DOI: | 10.1073/pnas.2315363121 |