Role of Ythdf2 in haematopoietic stem cell mRNA metabolism

Abstract

The RNA binding protein YTHDF2, which recognises and targets N6- methyladenosie (m6A) modified mRNA for degradation, has emerged as a novel and exciting target. In mouse, deletion of YTHDF2 results in an expansion and improvement of normal haematopoietic stem cells (HSC) but blocks leukemogenesis, indicating potential uses for stem cell expansion or leukaemia treatment. Using haematopoietic specific murine models of Ythdf2 deletion, I show that at a young age Ythdf2 deficient HSCs are expanded and have improved reconstitution following transplantation. RNA-seq and m6A- seq in HSCs identified upregulation of m6A modified inflammatory transcripts, indicating failure in their degradation pathway. Furthermore, upon stress or age, Ythdf2 deficiency results in hallmarks of chronic inflammation including a myeloid bias, extramedullary haematopoiesis and HSC exhaustion. Induction of inflammation induces expression of YTHDF2, indicating a role in inflammatory resolution. From this I suggest that YTHDF2 dependent degradation of inflammatory transcripts is a novel negative feedback mechanism by which stem cells can protect themselves from chronic immune activation and retain their function.