期刊
SCIENCE ADVANCES
卷 6, 期 34, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aba0647
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资金
- National Key Research and Development Program of China [2017YFA0103800, 2019YFA0802202]
- National Natural Science Foundation of China [81901601, 81972651, 31771630, 81702784, 31970700]
- Guangdong Innovative and Entrepreneurial Research Team Program [2016ZT06S029]
- Natural Science Foundation of Guangdong Province [2019A1515011111, 2017A030312009]
- Guangdong Basic and Applied Basic Researh Foundation [2018A030313370]
While N-6-methyladenosine (m(6)A) 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 m(6)A 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 m(6)A cotranscriptionally. Mechanistically, the mRNA of lysine demethylase 6B (KDM6B) was m(6)A-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 m(6)A modification during transcription. KDM6B recruits the m(6)A methyltransferase complex to facilitate the methylation of m(6)A in transcribing mRNA by removing adjacent H3K27me3 barriers. These results revealed cross-talk between m(6)A and H3K27me3 during bacterial infection, which has broader implications for deciphering epitranscriptomics in immune homeostasis.
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