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

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.