小柯机器人

近日，美国贝勒医学院Katherine Y. King及其研究小组发现，慢性感染通过IFNγ信号驱动Dnmt3a功能丧失的克隆性造血作用。这一研究成果于2021年3月19日在线发表在国际学术期刊《细胞—干细胞》上。

研究人员表示，年龄相关的克隆性造血（CH）是恶性肿瘤、心血管疾病和全因死亡率的危险因素。DNMT3A中的体细胞突变是CH的驱动力，但突变和CH的获得之间可能需要数十年的时间，这表明环境因素有助于克隆扩增。

研究人员测试了感染是否提供促进小鼠嵌合体中Dnmt3a突变造血干细胞（HSCs）扩增的选择性压力。通过将Dnmt3a^-/-和WT HSC移植到WT小鼠中，研究人员创建了Dnmt3a-mosaic小鼠，并观察到在慢性分枝杆菌感染期间Dnmt3a^-/-HSCs的实质性扩增。单独注射重组IFNγ足以在感染后通过Dnmt3a^-/-HSCs对CH进行表型重现。

转录和表观遗传学特征分析和功能研究表明，与广泛甲基化改变相关的分化减少，而继发性应激诱导的凋亡减少则是感染期间Dnmt3a^-/-克隆扩增的原因。DNMT3A突变型人类HSC相似地表现出缺陷的IFNγ诱导分化。因此，研究人员证明了在慢性感染期间诱导的IFNγ信号可以驱动DNMT3A功能丧失的CH。 

附：英文原文

Title: Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling

Author: Daniel Hormaechea-Agulla, Katie A. Matatall, Duy T. Le, Bailee Kain, Xiaochen Long, Pawel Kus, Roman Jaksik, Grant A. Challen, Marek Kimmel, Katherine Y. King

Issue&Volume: 2021-03-19

Abstract: Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovasculardisease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation andCH, suggesting that environmental factors contribute to clonal expansion. We testedwhether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras. We created Dnmt3a-mosaic mice by transplanting Dnmt3a/ and WT HSCs into WT mice and observed the substantial expansion of Dnmt3a/ HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alonewas sufficient to phenocopy CH by Dnmt3a/ HSCs upon infection. Transcriptional and epigenetic profiling and functional studiesindicate reduced differentiation associated with widespread methylation alterations,and reduced secondary stress-induced apoptosis accounts for Dnmt3a/ clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFNγ-induced differentiation. We thusdemonstrate that IFNγ signaling induced during chronic infection can drive DNMT3A-loss-of-functionCH.

DOI: 10.1016/j.stem.2021.03.002

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00108-9

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