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

Abstract

While <i>N</i> 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 (<i>KDM6B</i>) was m⁶A-modified and its decay mediated by YTHDF2. <i>YTHDF2</i> deficiency stabilized <i>KDM6B</i> 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.