Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity [ChIP-seq]
A deeper understanding of the processes that sustain long-term reprogramming of rapidly turned-over cells in humans can offer unprecedented therapeutic potential, especially for immune cells like neutrophils, given their short lifespan in circulation and importance in both acute and chronic diseases. Hypoxia is a hallmark of a plethora of disease states and significantly shapes neutrophil effector functions. However, its potential contribution to long-term neutrophil reprogramming remains largely unexplored. We have observed persistent perturbations in newly formed circulating neutrophils' phenotype and function in patients 3-6 months following hospitalisation with acute respiratory distress syndrome (ARDS), where poor oxygenation takes place.  These lasting changes are associated with widespread loss of H3K4me3 in genomic regions of relevance to neutrophil activities. Notably, the replication of these findings in healthy volunteers months following altitude-induced hypoxaemia attributes a role to the oxygen deprivation as a driver for long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal deleterious outcomes for infection and show that persistent loss of H3K4me3 originates in proNeu and preNeu populations within the bone marrow and is linked to hypoxia-driven n-terminal histone 3 clipping. Thus, we present novel evidence that acute adaptations to systemic hypoxia trigger central changes in newly formed neutrophil populations, resulting in long-term impairment of effector functions and placing hypoxia as a crucial orchestrator of sustained neutrophil reprogramming. Overall design: We used ChIP-seq to determine locus-specific changes in H3K4me3 levels across the genome in circulating neutrophils from healthy donors and survivors from acute respiratory distress syndrome (ARDS) 3-6 months after hospital admission