Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-10-24 DOI:10.1126/science.ado6836

Julia Phan, Brandon Chen, Zhiyu Zhao, Gabriele Allies, Antonella Iannaccone, Animesh Paul, Feyza Cansiz, Alberto Spina, Anna-Sophia Leven, Alexandra Gellhaus, Dirk Schadendorf, Rainer Kimmig, Marcel Mettlen, Alpaslan Tasdogan, Sean J. Morrison

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Abstract

Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and LINE elements. Retrotransposon transcription activates the innate immune sensors cyclic GMP-AMP synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in non-pregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN regulated genes were also induced in mouse HSCs after serial bleeding and in human HSCs during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant, but not non-pregnant, people suggesting conservation of these mechanisms from mice to humans.

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逆转录转座子共同激活造血干细胞和红细胞生成过程

造血干细胞（HSCs）和红细胞生成在妊娠期和出血后通过逆转录转座子（包括内源性逆转录病毒和LINE元件）的去抑制而被激活。逆转录病毒转录激活先天性免疫感应器环形 GMP-AMP 合成酶（cGAS）和干扰素（IFN）基因刺激器（STING），从而诱导造血干细胞中的 IFN 和 IFN 调控基因，增加造血干细胞的分裂和红细胞生成。抑制逆转录酶或缺乏 cGAS 或 STING 对非妊娠小鼠的造血几乎没有影响，但却会耗尽妊娠小鼠的造血干细胞和红细胞祖细胞，从而降低红细胞数量。在连续出血后的小鼠造血干细胞和怀孕期间的人类造血干细胞中，逆转录酶载体和 IFN 调控基因也被诱导。逆转录酶抑制剂的使用与妊娠期贫血有关，但与非妊娠期贫血无关，这表明这些机制从小鼠到人类都是相同的。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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