Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cells
CD4+ regulatory T cells (TREGS) are critical for immune tolerance and the transcription factor Forkhead Box P3 (FOXP3) plays a crucial role in their differentiation and function. Recently, an alternative promoter has been reported for FOXP3, which is active only in TREGS and could have profound impl...
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| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | RNA Biology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15476286.2025.2502719 |
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| author | Marcos Cases Niclas Ritter Hector Rincon-Arevalo Sandy Kroh Aysegül Adam Marieluise Kirchner Hanieh Moradian Manfred Gossen Maria Dzamukova Artür Manukyan Markus Landthaler Christopher Kressler Anja E. Hauser Daniel P. Depledge Julia K. Polansky Hyun-Dong Chang |
| author_facet | Marcos Cases Niclas Ritter Hector Rincon-Arevalo Sandy Kroh Aysegül Adam Marieluise Kirchner Hanieh Moradian Manfred Gossen Maria Dzamukova Artür Manukyan Markus Landthaler Christopher Kressler Anja E. Hauser Daniel P. Depledge Julia K. Polansky Hyun-Dong Chang |
| author_sort | Marcos Cases |
| collection | DOAJ |
| description | CD4+ regulatory T cells (TREGS) are critical for immune tolerance and the transcription factor Forkhead Box P3 (FOXP3) plays a crucial role in their differentiation and function. Recently, an alternative promoter has been reported for FOXP3, which is active only in TREGS and could have profound implications for the output of the locus, and therefore, for the functionality of these cells. By direct RNA sequencing we identified multiple novel FOXP3 transcriptional products, including one relatively abundant isoform with an extended 5’ UTR that we named ‘longFOXP3’. Western blotting, analysis of public mass spectrometry data, and transfection of in vitro transcribed RNA suggested that longFOXP3 is not coding. Furthermore, we show using two distinct RNA single-molecule fluorescence in situ hybridization technologies that transcription from the upstream promoter correlates with decreased levels of FOXP3 at the mRNA and protein levels. Together, we provide compelling evidence that the transcriptional output of the human FOXP3 locus is far more complex than that of the current annotation and warrants a more detailed analysis to identify coding and non-coding transcript isoforms. Furthermore, the alternative promoter may interfere with the activity of the canonical promoter, evoking intragenic transcriptional interference, and in this way, fine-tune the levels of FOXP3 in human TREGS. |
| format | Article |
| id | doaj-art-3cb376d8b97c4a7ca1d1667d54c6c4e1 |
| institution | Matheson Library |
| issn | 1547-6286 1555-8584 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | RNA Biology |
| spelling | doaj-art-3cb376d8b97c4a7ca1d1667d54c6c4e12025-07-03T04:35:31ZengTaylor & Francis GroupRNA Biology1547-62861555-85842025-12-0122112010.1080/15476286.2025.2502719Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cellsMarcos Cases0Niclas Ritter1Hector Rincon-Arevalo2Sandy Kroh3Aysegül Adam4Marieluise Kirchner5Hanieh Moradian6Manfred Gossen7Maria Dzamukova8Artür Manukyan9Markus Landthaler10Christopher Kressler11Anja E. Hauser12Daniel P. Depledge13Julia K. Polansky14Hyun-Dong Chang15Flow Cytometry Core Facility, Deutsches Rheuma-Forschungszentrum Berlin, A Leibniz Institute (DRFZ), Berlin, GermanyInstitute of Virology, Hannover Medical School, Hannover, GermanyDepartment of Medicine, Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, GermanyDivision of Rheumatology and Clinical Immunology, Charité, Universitätsmedizin Berlin, Berlin, GermanyImmune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), A Leibniz Institute, Berlin, GermanyCore Unit Proteomics, Berlin Institute of Health at Charité- Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), Berlin, GermanyInstitute of Active Polymers, Helmholtz-Zentrum Hereon, Teltow, GermanyInstitute of Active Polymers, Helmholtz-Zentrum Hereon, Teltow, GermanyDeutsches Rheuma-Forschungszentrum Berlin, Ein Institut der Leibniz-Gemeinschaft, Berlin, GermanyBerlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, GermanyBerlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, GermanyBerlin Institute of Health (BIH) at Charité Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics Group, Berlin, GermanyDivision of Rheumatology and Clinical Immunology, Charité, Universitätsmedizin Berlin, Berlin, GermanyInstitute of Virology, Hannover Medical School, Hannover, GermanyBerlin Institute of Health (BIH) at Charité Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics Group, Berlin, GermanySchwiete laboratory for microbiota and inflammation, DRFZ, Berlin, GermanyCD4+ regulatory T cells (TREGS) are critical for immune tolerance and the transcription factor Forkhead Box P3 (FOXP3) plays a crucial role in their differentiation and function. Recently, an alternative promoter has been reported for FOXP3, which is active only in TREGS and could have profound implications for the output of the locus, and therefore, for the functionality of these cells. By direct RNA sequencing we identified multiple novel FOXP3 transcriptional products, including one relatively abundant isoform with an extended 5’ UTR that we named ‘longFOXP3’. Western blotting, analysis of public mass spectrometry data, and transfection of in vitro transcribed RNA suggested that longFOXP3 is not coding. Furthermore, we show using two distinct RNA single-molecule fluorescence in situ hybridization technologies that transcription from the upstream promoter correlates with decreased levels of FOXP3 at the mRNA and protein levels. Together, we provide compelling evidence that the transcriptional output of the human FOXP3 locus is far more complex than that of the current annotation and warrants a more detailed analysis to identify coding and non-coding transcript isoforms. Furthermore, the alternative promoter may interfere with the activity of the canonical promoter, evoking intragenic transcriptional interference, and in this way, fine-tune the levels of FOXP3 in human TREGS.https://www.tandfonline.com/doi/10.1080/15476286.2025.2502719FOXP3TREGalternative promotertranscript isoformtranscriptional interference |
| spellingShingle | Marcos Cases Niclas Ritter Hector Rincon-Arevalo Sandy Kroh Aysegül Adam Marieluise Kirchner Hanieh Moradian Manfred Gossen Maria Dzamukova Artür Manukyan Markus Landthaler Christopher Kressler Anja E. Hauser Daniel P. Depledge Julia K. Polansky Hyun-Dong Chang Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cells RNA Biology FOXP3 TREG alternative promoter transcript isoform transcriptional interference |
| title | Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cells |
| title_full | Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cells |
| title_fullStr | Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cells |
| title_full_unstemmed | Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cells |
| title_short | Novel non-coding FOXP3 transcript isoform associated to potential transcriptional interference in human regulatory T cells |
| title_sort | novel non coding foxp3 transcript isoform associated to potential transcriptional interference in human regulatory t cells |
| topic | FOXP3 TREG alternative promoter transcript isoform transcriptional interference |
| url | https://www.tandfonline.com/doi/10.1080/15476286.2025.2502719 |
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