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

Area of Science:

• Epigenetics
• Molecular Biology
• Immunology

Background:

• Transcriptional fidelity is crucial for cellular function, preventing the production of aberrant RNAs.
• Mechanisms ensuring accurate transcription and the consequences of spurious transcripts remain incompletely understood.

Purpose of the Study:

• To investigate the role of TET3 in maintaining transcriptional fidelity in airway smooth muscle cells.
• To elucidate the impact of TET3-dependent 5-hydroxymethylcytosine (5hmC) production on cellular signaling and airway inflammation.

Main Methods:

• Utilized airway smooth muscle cells to study TET3 function and 5hmC production.
• Analyzed the effects of TET3 loss on RNA polymerase II activity and transcript generation.
• Investigated the role of spurious transcripts in activating nucleic-acid-sensing pathways (TLR7/8).

Main Results:

• TET3 prevents aberrant RNA polymerase II entry into highly expressed genes by producing 5hmC.
• Loss of TET3 in smooth muscle cells leads to spurious transcripts that activate TLR7/8 signaling.
• This aberrant signaling provokes inflammation and airway remodeling, characteristic of asthma.
• Reduced 5hmC levels were observed in human asthma airways compared to controls.

Conclusions:

• TET3-mediated 5hmC production is essential for maintaining transcriptional accuracy in airway smooth muscle cells.
• Spurious transcription resulting from TET3 deficiency drives asthma-like inflammation and airway remodeling.
• Targeting spurious transcription may offer a therapeutic strategy for chronic airway inflammation in asthma.