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

Abstract

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.