Aging-induced pseudouridine synthase 10 impairs hematopoietic stem cells

Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity and differentiation-bias towards myeloid lineage. However, the molecular mechanism behind it remains not fully understood. In this study, we evaluated the expression of 5 pseudouridine (?) synthases between young and aged HSCs, and observed that three of them are increased during aging. Functional evaluation assay reveals that enforced PUS10 and PUS7 recapitulate the phenotype aged HSCs. The increase of PUS10 in aged HSCs is due to aging-declined CRL4DCAF1-mediated ubiquitination degradation signaling. Mechanistically, the destructive role of enforced PUS10 on HSCs is not achieved by its ? synthases activity, but through miR139, dysfunction of which impairs the reconstitution capacity of HSCs. Consistently, we observed no difference of tRNA pseudouridylation profile between young and aged HSPCs, while enforced PUS10 alters the microRNA profile in HSCs. Targeted dysfunction of Pus10 results in compromises the self-renewal capacity of HSC. Overall design: Comparative microRNA expression profiling analysis of RNA-seq data for Vector and PUS10-OE HSCs.