Spurious transcription causing innate immune responses is prevented by 
5-hydroxymethylcytosine

Wu, Fan; Li, Xiang; Looso, Mario; Liu, Hang; Ding, Dong; Guenther, Stefan; Kuenne, Carsten; Liu, Shuya; Weissmann, Norbert; Boettger, Thomas; Atzberger, Ann; Kolahian, Saeed; Renz, Harald; Offermanns, Stefan; Gaertner, Ulrich; Potente, Michael; Zhou, Yonggang; Yuan, Xuejun; Braun, Thomas

doi:10.1038/s41588-022-01252-3

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Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine

MPG-Autoren

/persons/resource/persons224104

Wu, Fan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228662

Li, Xiang
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224384

Looso, Mario
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons251618

Liu, Hang
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons284386

Ding, Dong
Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224128

Guenther, Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224382

Kuenne, Carsten
Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228672

Liu, Shuya
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224044

Boettger, Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons228786

Atzberger, Ann
Facs Service, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224185

Offermanns, Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224364

Potente, Michael
Angiogenesis & Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224110

Zhou, Yonggang
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224106

Yuan, Xuejun
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224052

Braun, Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Zitation

Wu, F., Li, X., Looso, M., Liu, H., Ding, D., Guenther, S., et al. (2023). Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine. NATURE GENETICS, (2023; 55(1)), 100-111. doi:10.1038/s41588-022-01252-3.

Zitierlink: https://hdl.handle.net/21.11116/0000-000C-CB39-0

Zusammenfassung

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.