1. Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation.
- Author
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Cheung P, Schaffert S, Chang SE, Dvorak M, Donato M, Macaubas C, Foecke MH, Li TM, Zhang L, Coan JP, Schulert GS, Grom AA, Henderson LA, Nigrovic PA, Elias JE, Gozani O, Mellins ED, Khatri P, Utz PJ, and Kuo AJ
- Subjects
- Adolescent, Arthritis, Juvenile blood, Arthritis, Juvenile genetics, CRISPR-Cas Systems genetics, Cathepsin G genetics, Cathepsin G metabolism, Cell Differentiation genetics, Cell Nucleus metabolism, Child, Child, Preschool, Chromatin metabolism, Enzyme Assays, Epigenomics, Female, Gene Knockout Techniques, Humans, Jurkat Cells, Leukocyte Elastase genetics, Leukocyte Elastase metabolism, Leukocytes, Mononuclear immunology, Macrophages metabolism, Male, Myeloblastin genetics, Myeloblastin metabolism, Primary Cell Culture, Proteolysis, RNA-Seq, Recombinant Proteins genetics, Recombinant Proteins metabolism, THP-1 Cells, Young Adult, Arthritis, Juvenile immunology, Cell Differentiation immunology, Epigenesis, Genetic immunology, Histones metabolism, Leukocytes, Mononuclear metabolism, Macrophages immunology
- Abstract
Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) 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 H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN 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.
- Published
- 2021
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