HMGN5, a chromatin remodeling protein drives COPD susceptibility

A role for epigenetics in COPD susceptibility is emerging. We identified a new player, a chromatin remodeling protein called High Mobility Group Nucleosome Binding Domain 5 (HMGN5) to be crucial in COPD pathogenesis. HMGN5 binds to the nucleosomal core particle of chromatin, competing with histone H1, thus altering chromatin structure and function. Bulk transcriptomic analysis of COPD patients demonstrated a significant reduction in HMGN5 expression in the lungs compared to healthy. scRNAseq data and immunofluorescence analysis revealed HMGN5 to be located in proliferative ATII cells in humans and mice. B6 mice exposed to porcine pancreatic elastase (PPE), demonstrated a reduction in Hmgn5 expression at d28. HMGN5 deficient mice had greater impaired lung function compared to WT controls following PPE exposure with greater evidence of emphysema. Mechanistically, in vitro studies revealed that downregulation of HMGN5 with siRNA in A549 cells resulted in a significant delay in cell proliferation sensitizing cells towards ferroptotic cell death by upregulating ACSL4 and the downregulation of SLC7A11 as well as GPX4, cellular protectors against ferroptosis. This crucially delayed organoid development from pmATII cells devoid of HMGN5 by siRNA knock down. Taken together, we show for the first time, that in COPD lungs, epithelial cell proliferation is impaired in the absence of HMGN5 which in turn sensitizes these cells to undergo ferroptotic cell death driving emphysema development and progression in patients and mice. This data suggests a novel causal link between chromatin dynamics and emphysema development in COPD.