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Updated: Dec 10, 2025
Intra-tracheal Administration of Haemophilus influenzae in Mouse Models to Study Airway Inflammation
Published on: March 2, 2016
Interplay of m6A and H3K27 trimethylation restrains inflammation during bacterial infection
Chenglei Wu1,2, Weixin Chen1,2, Jincan He1,2
1RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Abstract:
While N 6-methyladenosine (m6A) is the most prevalent modification of eukaryotic messenger RNA (mRNA) involved in various cellular responses, its role in modulating bacteria-induced inflammatory response remains elusive. Here, we showed that loss of the m6A reader YTH-domain family 2 (YTHDF2) promoted demethylation of histone H3 lysine-27 trimethylation (H3K27me3), which led to enhanced production of proinflammatory cytokines and facilitated the deposition of m6A cotranscriptionally. Mechanistically, the mRNA of lysine demethylase 6B (KDM6B) was m6A-modified and its decay mediated by YTHDF2. YTHDF2 deficiency stabilized KDM6B to promote H3K27me3 demethylation of multiple proinflammatory cytokines and subsequently enhanced their transcription. Furthermore, we identified H3K27me3 as a barrier for m6A modification during transcription. KDM6B recruits the m6A methyltransferase complex to facilitate the methylation of m6A in transcribing mRNA by removing adjacent H3K27me3 barriers. These results revealed cross-talk between m6A and H3K27me3 during bacterial infection, which has broader implications for deciphering epitranscriptomics in immune homeostasis.
Insights
The m6A reader YTHDF2 regulates inflammatory responses by controlling KDM6B. Loss of YTHDF2 enhances cytokine production and m6A modification, revealing cross-talk between m6A and H3K27me3 in immunity.
Area of Science:
- Epitranscriptomics
- Molecular Biology
- Immunology
Background:
- N6-methyladenosine (m6A) is a prevalent mRNA modification influencing cellular responses.
- The role of m6A in bacteria-induced inflammation is not well understood.
Purpose of the Study:
- To investigate the function of the m6A reader YTHDF2 in bacteria-induced inflammatory response.
- To elucidate the interplay between m6A and histone modifications in immune regulation.
Main Methods:
- Investigated the impact of YTHDF2 deficiency on inflammatory cytokine production.
- Analyzed the m6A modification and demethylation of histone H3 lysine-27 trimethylation (H3K27me3).
- Examined the role of lysine demethylase 6B (KDM6B) in regulating m6A and H3K27me3.
Main Results:
- Loss of YTHDF2 enhanced proinflammatory cytokine production and m6A deposition.
- YTHDF2 deficiency stabilized KDM6B, promoting H3K27me3 demethylation and cytokine transcription.
- H3K27me3 acts as a barrier to m6A modification during transcription, with KDM6B facilitating m6A deposition.
Conclusions:
- Revealed a novel cross-talk between m6A and H3K27me3 during bacterial infection.
- Demonstrated YTHDF2's critical role in modulating inflammatory responses through KDM6B.
- Highlighted the broader implications for understanding epitranscriptomics in immune homeostasis.
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