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Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine
Generation of functional transcripts requires transcriptional initiation at regular start sites, avoiding production of aberrant and potentially hazardous aberrant RNAs. The mechanisms maintaining transcriptional fidelity and the impact of spurious transcripts on cellular physiology and organ functi...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839451/ https://www.ncbi.nlm.nih.gov/pubmed/36539616 http://dx.doi.org/10.1038/s41588-022-01252-3 |
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author | Wu, Fan Li, Xiang Looso, Mario Liu, Hang Ding, Dong Günther, Stefan Kuenne, Carsten Liu, Shuya Weissmann, Norbert Boettger, Thomas Atzberger, Ann Kolahian, Saeed Renz, Harald Offermanns, Stefan Gärtner, Ulrich Potente, Michael Zhou, Yonggang Yuan, Xuejun Braun, Thomas |
author_facet | Wu, Fan Li, Xiang Looso, Mario Liu, Hang Ding, Dong Günther, Stefan Kuenne, Carsten Liu, Shuya Weissmann, Norbert Boettger, Thomas Atzberger, Ann Kolahian, Saeed Renz, Harald Offermanns, Stefan Gärtner, Ulrich Potente, Michael Zhou, Yonggang Yuan, Xuejun Braun, Thomas |
author_sort | Wu, Fan |
collection | PubMed |
description | Generation of functional transcripts requires transcriptional initiation at regular start sites, avoiding production of aberrant and potentially hazardous aberrant RNAs. The mechanisms maintaining transcriptional fidelity and the impact of spurious transcripts on cellular physiology and organ function have not been fully elucidated. Here we show that TET3, which successively oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other derivatives, prevents aberrant intragenic entry of RNA polymerase II pSer5 into highly expressed genes of airway smooth muscle cells, assuring faithful transcriptional initiation at canonical start sites. Loss of TET3-dependent 5hmC production in SMCs results in accumulation of spurious transcripts, which stimulate the endosomal nucleic-acid-sensing TLR7/8 signaling pathway, thereby provoking massive inflammation and airway remodeling resembling human bronchial asthma. Furthermore, we found that 5hmC levels are substantially lower in human asthma airways compared with control samples. Suppression of spurious transcription might be important to prevent chronic inflammation in asthma. |
format | Online Article Text |
id | pubmed-9839451 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-98394512023-01-15 Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine Wu, Fan Li, Xiang Looso, Mario Liu, Hang Ding, Dong Günther, Stefan Kuenne, Carsten Liu, Shuya Weissmann, Norbert Boettger, Thomas Atzberger, Ann Kolahian, Saeed Renz, Harald Offermanns, Stefan Gärtner, Ulrich Potente, Michael Zhou, Yonggang Yuan, Xuejun Braun, Thomas Nat Genet Article Generation of functional transcripts requires transcriptional initiation at regular start sites, avoiding production of aberrant and potentially hazardous aberrant RNAs. The mechanisms maintaining transcriptional fidelity and the impact of spurious transcripts on cellular physiology and organ function have not been fully elucidated. Here we show that TET3, which successively oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and other derivatives, prevents aberrant intragenic entry of RNA polymerase II pSer5 into highly expressed genes of airway smooth muscle cells, assuring faithful transcriptional initiation at canonical start sites. Loss of TET3-dependent 5hmC production in SMCs results in accumulation of spurious transcripts, which stimulate the endosomal nucleic-acid-sensing TLR7/8 signaling pathway, thereby provoking massive inflammation and airway remodeling resembling human bronchial asthma. Furthermore, we found that 5hmC levels are substantially lower in human asthma airways compared with control samples. Suppression of spurious transcription might be important to prevent chronic inflammation in asthma. Nature Publishing Group US 2022-12-20 2023 /pmc/articles/PMC9839451/ /pubmed/36539616 http://dx.doi.org/10.1038/s41588-022-01252-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wu, Fan Li, Xiang Looso, Mario Liu, Hang Ding, Dong Günther, Stefan Kuenne, Carsten Liu, Shuya Weissmann, Norbert Boettger, Thomas Atzberger, Ann Kolahian, Saeed Renz, Harald Offermanns, Stefan Gärtner, Ulrich Potente, Michael Zhou, Yonggang Yuan, Xuejun Braun, Thomas Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine |
title | Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine |
title_full | Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine |
title_fullStr | Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine |
title_full_unstemmed | Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine |
title_short | Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine |
title_sort | spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839451/ https://www.ncbi.nlm.nih.gov/pubmed/36539616 http://dx.doi.org/10.1038/s41588-022-01252-3 |
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