Courvan, E. M. C. | bioRxiv Science

bioRxiv2026

m6A depletion attenuates the macrophage type I interferon response

Macrophages play an important role in coordinating the antiviral response and post-transcriptional regulation of mRNA is an important element of the inflammatory gene expression required for defense against viral pathogens. N6-methyladenosine (m6A) deposition on mRNA by METTL3 constitutes one such post-transcriptional event which facilitates a cascade of downstream regulation via RNA decay and translation. We discovered that in THP1-derived and peripheral blood macrophages, m6A depletion with the METTL3 inhibitor STM2457 leads to enhanced proliferation of the human coronavirus OC43. Using TimeLapse-seq to comprehensively measure changes in abundance, RNA decay and transcription, we find that STM2457 downregulates the interferon response far upstream by reducing expression of both the type I interferon receptor and STAT1. We conclude that macrophages depend on m6A to support expression of interferon sensing machinery and in m6As absence, fail to mount as strong of a type I interferon response.

immunology↗

bioRxiv2023

Post-transcriptional control contributes to hypoxia induced tumorigenic phenotypes in macrophages

Macrophages are effector immune cells that experience substantial changes to oxygenation when transiting through tissues, especially when entering tumors or infected wounds. How the transition to hypoxia alters gene expression and macrophage effector function remains poorly understood, especially at the post-transcriptional level. Here we use TimeLapse-seq to measure how hypoxia modifies inflammatory activation of primary macrophages. Nucleoside recoding sequencing allowed us to derive steady-state transcript levels, degradation rates, and transcriptional synthesis rates from the same dataset. We find that inflammatory activation of macrophages is altered by hypoxia due to increased mRNA decay. Destabilized transcripts encode for proteins associated with phagocytosis and proteolysis of the extracellular matrix. Consistent with differential gene expression, we observed hypoxia alters the specificity of macrophage phagocytosis and reduces their invasion of extracellular matrix. Hypoxic gene expression bears similarity to tumorigenic macrophages in solid tumor biopsies suggesting post-transcriptional control contributes to the macrophage transition from tumoricidal to tumorigenic.

immunology↗