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C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2020-03-12 , DOI: 10.1016/j.stem.2020.01.017
Bérengère de Laval 1 , Julien Maurizio 2 , Prashanth K Kandalla 3 , Gabriel Brisou 1 , Louise Simonnet 1 , Caroline Huber 1 , Gregory Gimenez 4 , Orit Matcovitch-Natan 5 , Susanne Reinhardt 6 , Eyal David 5 , Alexander Mildner 7 , Achim Leutz 8 , Bertrand Nadel 1 , Christophe Bordi 9 , Ido Amit 5 , Sandrine Sarrazin 1 , Michael H Sieweke 10
Affiliation  

Hematopoietic stem cells (HSCs) maintain life-long production of immune cells and can directly respond to infection, but sustained effects on the immune response remain unclear. We show that acute immune stimulation with lipopolysaccharide (LPS) induced only transient changes in HSC abundance, composition, progeny, and gene expression, but persistent alterations in accessibility of specific myeloid lineage enhancers occurred, which increased responsiveness of associated immune genes to secondary stimulation. Functionally, this was associated with increased myelopoiesis of pre-exposed HSCs and improved innate immunity against the gram-negative bacterium P. aeruginosa. The accessible myeloid enhancers were enriched for C/EBPβ targets, and C/EBPβ deletion erased the long-term inscription of LPS-induced epigenetic marks and gene expression. Thus, short-term immune signaling can induce C/EBPβ-dependent chromatin accessibility, resulting in HSC-trained immunity, during secondary infection. This establishes a mechanism for how infection history can be epigenetically inscribed in HSCs as an integral memory function of innate immunity.

中文翻译:

C/EBPβ依赖性表观遗传记忆诱导造血干细胞的训练免疫。

造血干细胞 (HSC) 维持免疫细胞的终生生产,并可以直接对感染作出反应,但对免疫反应的持续影响仍不清楚。我们表明,脂多糖 (LPS) 的急性免疫刺激仅诱导 HSC 丰度、组成、后代和基因表达的短暂变化,但特定骨髓谱系增强子的可及性发生持续改变,这增加了相关免疫基因对二次刺激的反应性。在功能上,这与预先暴露的 HSC 的骨髓生成增加和对革兰氏阴性细菌铜绿假单胞菌的先天免疫增强有关。可获得的骨髓增强子富含 C/EBPβ 靶标,而 C/EBPβ 缺失消除了 LPS 诱导的表观遗传标记和基因表达的长期记录。因此,短期免疫信号可以诱导 C/EBPβ 依赖的染色质可及性,从而在继发感染期间产生 HSC 训练的免疫。这建立了一种机制,即感染史如何在 HSC 中作为先天免疫的完整记忆功能进行表观遗传铭刻。
更新日期:2020-03-12
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