ena-STUDY-INSTITUT PASTEUR-22-02-2018-14:11:45:840-100
Impact of gut microbiota on m6A epitranscriptomic mRNA modifications in host tissues
Epitranscriptomic modifications of mRNA have recently been discovered to represent a new layer of regulation for gene expression1,2. N6-methyl adenosine (m6A) modification of mRNA is a dynamic process regulated by the activity of methyltransferases, mainly METTL3, and the demethylases Alkbh5 and FTO. m6A modifications can either accelerate mRNA degradation or increase initiation of mRNA translation3. Gene expression is also regulated by the intestinal microbiota through its effects on the host transcriptome and proteome influencing tissue morphology, metabolism, host immune response to pathogens, and even behaviour4-8. For many of these microbiota-regulated events, the precise underlying regulatory mechanisms are unknown. Using m6A-methylated mRNA immunoprecipitation and sequencing (MeRIP-Seq) we analysed the effect of gut microbiota on host m6A modifications in both the proximal colon and liver in various mouse models. This led to the identification of differentially methylated transcripts specifically influenced by the microbiota in both tissues. In conclusion, we could demonstrate for the first time that the gut microbiota regulates posttranscriptional mRNA modifications in the host in addition to its known effects on transcription. These findings highlight a new and unsuspected level of interaction in the complex interplay between commensal bacteria and their host organism.
Epitranscriptomic modifications of mRNA have recently been discovered to represent a new layer of regulation for gene expression1,2. N6-methyl adenosine (m6A) modification of mRNA is a dynamic process regulated by the activity of methyltransferases, mainly METTL3, and the demethylases Alkbh5 and FTO. m6A modifications can either accelerate mRNA degradation or increase initiation of mRNA translation3. Gene expression is also regulated by the intestinal microbiota through its effects on the host transcriptome and proteome influencing tissue morphology, metabolism, host immune response to pathogens, and even behaviour4-8. For many of these microbiota-regulated events, the precise underlying regulatory mechanisms are unknown. Using m6A-methylated mRNA immunoprecipitation and sequencing (MeRIP-Seq) we analysed the effect of gut microbiota on host m6A modifications in both the proximal colon and liver in various mouse models. This led to the identification of differentially methylated transcripts specifically influenced by the microbiota in both tissues. In conclusion, we could demonstrate for the first time that the gut microbiota regulates posttranscriptional mRNA modifications in the host in addition to its known effects on transcription. These findings highlight a new and unsuspected level of interaction in the complex interplay between commensal bacteria and their host organism.