Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here Kuo and colleagues uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development. Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3 Delta N) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3 Delta N distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3 Delta N is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3 Delta N loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3 Delta N is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

Automated summary

The study uncovers an epigenetic mechanism that primes chromatin for macrophage development by repressing histone H3 proteolytic cleavage during monocyte-to-macrophage transition. The histone mark is catalyzed by neutrophil serine proteases, which are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3 Delta N distribution across the genome, largely undetectable in fully differentiated macrophages, suggesting its role in regulating gene expression reprogramming.