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

Abstract

While N6-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.

Regulation of RNA N6-methyladenosine modification and its emerging roles in skeletal muscle development

“…Moreover, H3K27me3 is also a barrier to m 6 A modification during transcription. These results suggest an interplay between m 6 A and H3K27me3 during bacterial infection [42]. In addition, a recent study suggested that the gut microbiota affects the m 6 A epitranscriptome of mouse cecum and liver, mediating pathways related to metabolism, inflammation, and antimicrobial response [43].…”

“…Genome-wide m 6 A methylation analysis has suggested that there is an interaction between m 6 A modification and other post-transcriptional regulatory modifications [40][41][42][43]. m 6 A methylation and adenosine-inosine (A-to-I) editing are two distinct and abundant RNA modifications at adenosine, between which there exists a negative correlation.…”

Transcriptome-Wide m6A Methylation in Skin Lesions From Patients With Psoriasis Vulgaris

“…For example, silencing of m 6 A writers (METTL3, METTL14, or WTAP) in mammalian cells has been shown to lead to increases in the abundance of their respective target transcripts (Liu et al, 2014). Overexpression of m 6 A reader (YTHDF2) in human embryonic kidney 293T cells has been shown to lead to decreases in the abundance of the target transcripts (Wu et al, 2020). Besides, m 6 A methylation was shown to be positively correlated with mRNA level when m 6 A methylation was linked to enhance mRNA expression (Zhao et al, 2017).…”

N6-Methyladenosine, DNA Repair, and Genome Stability

“…Moreover, m 6 A can interplay with histone modifications by regulating the expression of histone modification enzymes. m 6 A on the mRNA of lysine demethylase 6B (KDM6B) is bound by YTHDF2, causing the degradation of KDM6B mRNAs, reducing the KDM6B protein level, and resulting in a high level of H3K27me3 in proinflammatory cytokine gene like IL6 (Wu et al, 2020). Also, m 6 A can specifically increase the protein level rather than the mRNA level of the histone methyltransferase to stimulate the trimethylation of H3K27 (Chen et al, 2019).…”