Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Nat Immunol. 2021 Jun;22(6):711-722. doi: 10.1038/s41590-021-00928-y. Epub 2021 May 20.
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.
染色质在免疫细胞分化过程中经历广泛的重编程。在这里，我们报告在单核细胞向巨噬细胞发育过程中控制组蛋白 H3 氨基末端蛋白水解切割（H3ΔN）的抑制。这种在人外周血单核细胞中丰富的组蛋白标记由中性粒细胞丝氨酸蛋白酶（NSP）组织蛋白酶 G、中性粒细胞弹性蛋白酶和蛋白酶 3 催化。随着单核细胞成熟为巨噬细胞，NSP 受到抑制。综合表观基因组分析显示，在单核细胞系和原代单核细胞中，H3ΔN 广泛分布在基因组上，而在完全分化的巨噬细胞中则几乎无法检测到。H3ΔN 富含于有活性转录基因的开放染色质上。在单核细胞中同时耗尽 NSP 会导致 H3ΔN 丢失，并进一步增加染色质可及性，这可能为基因表达重编程做好染色质准备。重要的是，全身性幼年特发性关节炎（一种以巨噬细胞大量参与为特征的自身炎症性疾病）患者的单核细胞中 H3ΔN 减少。总的来说，我们揭示了一种表观遗传机制，该机制使染色质为促进巨噬细胞发育做好准备。
