N6-Methyladenosine Promotes TNF mRNA Degradation In CD4+ T Lymphocytes

J Leukoc Biol. 2024 Apr 24:qiae087. doi: 10.1093/jleuko/qiae087. Online ahead of print.ABSTRACTN6-methyladenosine (m6A) is a RNA modification that can regulate post-transcriptional processes including RNA stability, translation, splicing and nuclear export. In CD4+ lymphocytes, m6A modifications have been demonstrated to play a role in early differentiation processes. The role of m6A in CD4+ T cell activation and effector function remains incompletely understood. To assess the role of m6A in CD4+ T lymphocyte activation and function, we assessed the transcriptome-wide m6A landscape of human primary CD4+ T cells by methylated RNA immunoprecipitation (meRIP) sequencing. Stimulation of the T cells impacted the m6A pattern of hundreds of transcripts including tumor necrosis factor (TNF). m6A methylation was increased on TNF mRNA after activation, predominantly in the 3' untranslated region (UTR) of the transcript. Manipulation of m6A levels in primary human T cells, the directly affected the expression of TNF. Furthermore, we identified that the m6A reader protein YT521-B homology domain family-2 (YTHDF2) binds m6A-methylated TNF mRNA, and promotes its degradation. Taken together, this study demonstrates that TNF expression in CD4+ T lymphocytes is regulated via m6A and YTHDF2, thereby providing novel insight into the regulation of T cell effector functions.PMID:38657004 | DOI:10.1093/jleuko/qiae087

Source: Journal of Leukocyte Biology - April 24, 2024 Category: Hematology Authors: Ellen C N van Vroonhoven Lucas W Picavet Rianne C Scholman Lyanne J P M Sijbers Corlinda R E Kievit Noortje A M van den Dungen Michal Mokry Anouk Evers Robert J Lebbink Enric Mocholi Paul J Coffer Jorg J A Calis Sebastiaan J Vastert Jorg van Loosdregt Source Type: research