Interplay of m 6 A and H3K27 trimethylation restrains inflammation during bacterial infection.

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.