A1 Refereed original research article in a scientific journal
Long noncoding RNA LIRIL2R modulates FOXP3 levels and suppressive function of human CD4+ regulatory T cells by regulating IL2RA
Authors: Andrabi, Syed Bilal Ahmad; Kalim, Ubaid Ullah; Palani, Senthil; Khan, Mohd Moin; Khan, Meraj Hasan; Fagersund, Jimmy; Orpana, Julius; Paulin, Niklas; Batkulwar, Kedar; Junttila, Sini; Buchacher, Tanja; Grönroos, Toni; Toikka, Lea; Ammunet, Tea; Sen, Partho; Orešič, Matej; Kumpulainen, Venla; Tuomisto, Johanna E. E.; Sinha, Rahul; Marson, Alexander; Rasool, Omid; Elo, Laura L.; Lahesmaa, Riitta
Publisher: National Academy of Sciences
Publication year: 2024
Journal: Proceedings of the National Academy of Sciences of the United States of America
Journal name in source: Proceedings of the National Academy of Sciences of the United States of America
Journal acronym: Proc Natl Acad Sci U S A
Article number: e2315363121
Volume: 121
Issue: 23
ISSN: 0027-8424
eISSN: 1091-6490
DOI: https://doi.org/10.1073/pnas.2315363121
Web address : https://www.pnas.org/doi/10.1073/pnas.2315363121
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/454736769
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.
Downloadable publication This is an electronic reprint of the original article. |  |
Funding information in the publication:
R.L. is supported by Centre of Excellence in Molecular Systems Immunology and Physiology Research (2012 to 2017) grant 250114; Academy of Finland grants 250114, 292335, 294337, 292482, 319280, 329277, 331793, 335435, and 31444; Juvenile Diabetes Research Foundation grant; the Novo Nordisk Foundation grant NNF19OC0057218; Jane and Aatos Erkko Foundation grant; and the Finnish Cancer Foundation grant. L.L.E. is supported by European Research Council ERC 677943, European Union’s Horizon 2020 research and innovation programme 955321; and Academy of Finland grants 310561, 314443, 329278, 335434, 335611, and 341342. R.L. and L.L.E. were supported by the Sigrid Juselius Foundation, Turku Graduate School University of Turku, Åbo Akademi University InFLAMES Flagship Programme of the Academy of Finland 337530, Biocenter Finland, and ELIXIR Finland.
