Non-canonical function of histone methyltransferase G9a in the translational regulation of chronic inflammation.

We report a novel translation-regulatory function of G9a, a histone methyltransferase and well-understood transcriptional repressor, in promoting hyperinflammation and lymphopenia; two hallmarks of endotoxin tolerance (ET)-associated chronic inflammatory complications. Using multiple approaches, we demonstrate that G9a interacts with multiple translation regulators during ET, particularly the N6-methyladenosine (m6A) RNA methyltransferase METTL3, to co-upregulate expression of certain m6A-modified mRNAs that encode immune-checkpoint and anti-inflammatory proteins. Mechanistically, G9a promotes m6A methyltransferase activity of METTL3 at translational/post-translational level by regulating its expression, its methylation, and its cytosolic localization during ET. Additionally, from a broader view extended from the G9a-METTL3-m6A translation regulatory axis, our translatome proteomics approach identified numerous "G9a-translated" proteins that unite the networks associated with inflammation dysregulation, T cell dysfunction, and systemic cytokine response. In sum, we identified a previously unrecognized function of G9a in protein-specific translation that can be leveraged to treat ET-related chronic inflammatory diseases. [Display omitted] • G9a interacts with distinct translation regulators to modulate protein translation • G9a-METTL3-m6A axis promotes hyper-inflammation and T cell dysfunction • G9a promotes turnover of chronic disease-related proteins in ET macrophages • G9a inhibition hinders proteostasis of chronic disease-related proteins Muneer et al. reveal that G9a—a histone methyltransferase and well-established transcriptional repressor—promotes macrophage proliferation, T cell depletion/dysfunction (lymphopenia), and organ-damaging "cytokine storm" (hyperinflammation) through its non-canonical/non-epigenetic function involving protein translation, a mechanism that can be leveraged to treat chronic inflammatory diseases including sepsis, ARDS, & COVID19. [ABSTRACT FROM AUTHOR]