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

• 成果类型: Article
• 署名作者: Phan, Julia; Chen, Brandon; Zhao, Zhiyu; Allies, Gabriele; Iannaccone, Antonella; Paul, Animesh; Cansiz, Feyza; Spina, Alberto; Leven, Anna-Sophia; Gellhaus, Alexandra; Schadendorf, Dirk; Kimmig, Rainer; Mettlen, Marcel; Tasdogan, Alpaslan; Morrison, Sean J.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Duisburg Essen; Helmholtz Association; German Cancer Research Center (DKFZ); University of Duisburg Essen; University of Duisburg Essen; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11787
• DOI: 10.1126/science.ado6836
• 发表日期: 2024-11-08
• 关键词: gmp-amp synthase; progenitor; receptors; ELEMENTS; sensor; hiv; expression; emergence; responses; trigger

摘要

Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and long interspersed nuclear elements. Retrotransposon transcription activates the innate immune sensors cyclic guanosine 3 ',5 '-monophosphate-adenosine 5 '-monophosphate 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 nonpregnant 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 in nonpregnant people, suggesting conservation of these mechanisms from mice to humans.