Functional Multi-Omics Reveals Noncanonical Function of G9a in Translational Regulation of Chronic Inflammation

Abstract

By largely unknown mechanisms, dysregulated gene-specific translation directly contributes to chronic inflammation-associated diseases such as sepsis and ARDS. Here, we report that G9a, a histone methyltransferase and well-regarded transcriptional repressor, non-canonically or non-epigenetically activates translation of select antimicrobial genes to promote proliferation of cytokine producing macrophages and to impair T cell function; all hallmarks of endotoxin-tolerance related complications including sepsis, ARDS and COVID19. Mechanistically, G9a interacts with translation regulators including METTL3, an N6-methyladenosine or m6A RNA methyltransferase, and methylates it to cooperatively upregulate the translation of certain m6A-modified mRNAs that encode immune checkpoint and anti-inflammatory proteins. Further, translatome proteomic analysis of ET macrophages progressively treated by a G9a inhibitor identified proteins showing G9a-dependent translation that unite the networks associated with hyperinflammation and T cell dysfunction. Overall, we identified a previously unrecognized function of G9a in gene-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases.