JAK2 signalling to HNRNPA1 represses retrotransposon activity in haematopoietic stem cells.

Abstract Retrotransposon expression must be tightly controlled, particularly in long-lived multipotent stem cells, to prevent deleterious consequences including insertional mutations. Several mechanisms are known to repress retrotransposon transcription during development which are generally thought to persist thereafter. However, integration of retrotransposable elements into host genomes has also provided a major source of genetic variation across evolution, generating many sequences that have acquired advantageous host functions. Physiological roles for retrotransposon sequences imply the existence of regulatory mechanisms responsive to cellular states and environments, but little is known about retrotransposon expression and mobility in adult stem cells or about how these processes might be dynamically regulated. Here we describe the landscape of retrotransposon expression and integration in human and mouse haematopoietic stem cells (HSCs). All HSCs express a broad range of retrotransposon transcripts, including LINEs, SINEs and endogenous retroviruses. Using novel computational tools, we find that retrotransposons cause fewer somatic insertional mutations in HSCs than in intestinal stem cells, and mice unexpectedly accrue new retrotransposon insertions at a rate 350-fold higher than humans, indicating tissue-specific and evolutionary constraints on retrotransposon activity. We also identify a previously unrecognised pathway which links cytokine signalling, RNA-modulating HNRNP complexes and repression of retrotransposon activity. Activation of JAK2, by thrombopoietin or gain-of-function JAK2 mutations, triggers tyrosine phosphorylation of HNRNPA1 that represses expression of ERV, LINE and SINE retrotransposons and reduces insertional mutagenesis. This pathway allows dynamic regulation of retrotransposon activity in response to cellular context, and coordinates maximal repression of retrotransposons with cytokine-induced proliferation, protecting the HSC genome from the increased risk of retrotransposition that exists during cell division. This reflects a novel paradigm of retrotransposon repression that is dynamically regulated to peak while the cell is most vulnerable to insertional mutations, but minimises the impact on retrotransposon-derived sequences that have acquired host functions at other times. Furthermore, JAK2 is activated in multiple tissues by an array of cytokines and receptors, and HNRNP proteins are widely expressed. Pathways analogous to the one we describe here in HSCs are therefore likely to operate in other cell types to protect their genomes and allow dynamic regulation of retrotransposon activity.