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

• Published in: Science (American Association for the Advancement of Science) 2024-11, Vol.386 (6722), p.eado6836-eado6836
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Activation analysis; Adenosine monophosphate; AMP; Anemia; Anemia - genetics; Animals; Bleeding; Blood; Blood volume; Bone marrow; Cell activation; Cell differentiation; Cell division; Chromatin; Clonal deletion; Deoxyribonucleic acid; DNA; DNA damage; DNA structure; Erythrocytes; Erythropoiesis - genetics; Evolutionary genetics; Female; Gene expression; Gene sequencing; Gene silencing; Genes; Genetics; Genomes; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Hemopoiesis; Hemorrhage - genetics; Homeostasis; Humans; Individualized Instruction; Information processing; Injury prevention; Interferon; Interferons - genetics; Interferons - metabolism; Long Interspersed Nucleotide Elements; Mammals; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Nucleic acids; Nucleotide sequence; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Numbers; Pregnancy; Progenitor cells; Regeneration; Regeneration (physiology); Retroelements - genetics; Reverse transcription; Ribonucleic acid; RNA; Spleen; Stem cells; Stimulators; Stresses; Tissue engineering; Transcription, Genetic; Transcripts (Written Records)
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.ado6836

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.