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bioRxiv · 10.1101/742072

m6A methylation potentiates cytosolic dsDNA recognition in a sequence-specific manner

Balzarolo, M.·Engels, S.·de jong, A.·Franke, K.·van den Berg, T. K.·Janssen, E. M.·van Steensel, B.·Wolkers, M.
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Abstract

Nucleic acid sensing through pattern recognition receptors is critical for immune recognition of microbial infections. Microbial DNA is frequently methylated at the N6 position of adenines (m6A), a modification that is rare in mammalian host DNA. We show that m6A-methylation of 5-GATC-3 motifs augments the immunogenicity of double stranded (ds)DNA in macrophages and dendritic cells. Transfection with m6A-methylated DNA increased the expression of the activation markers CD69 and CD86, and of Ifn{beta}, iNos and Cxcl10 mRNA. Recognition of m6A DNA occurs independently of TLR and RIG-I signaling but requires STING, a key mediator of cytosolic DNA sensing. Intriguingly, the response to m6A DNA is sequence-specific. m6A is immunostimulatory in some motifs, but immunosuppressive in others, a feature that is conserved between mouse and human. In conclusion, epigenetic alterations of bacterial DNA are differentially perceived by innate cells, a feature that could potentially be used for the design of immune-modulating therapeutics.

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Balzarolo, M., Engels, S., de jong, A., Franke, K., van den Berg, T. K., Janssen, E. M., van Steensel, B., Wolkers, M.. 2019-08-21. m6A methylation potentiates cytosolic dsDNA recognition in a sequence-specific manner. https://doi.org/10.1101/742072

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