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 (Ψ) 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 Ψ 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. Comparative tRNA pseudouridylation profiling analysis of DM-Ψ-seq data for young and aged HSPCs.

衰老的造血干细胞（hematopoietic stem cells, HSCs）表现出造血重建能力受损以及向髓系谱系分化的偏倚。然而，其背后的分子机制尚未完全阐明。本研究检测了年轻与衰老HSCs中5种假尿苷（Ψ）合酶（pseudouridine (Ψ) synthases）的表达水平，发现其中3种在衰老过程中表达上调。功能验证实验显示，强制过表达PUS10与PUS7可重现衰老HSCs的表型。衰老HSCs中PUS10的表达上调，是由衰老介导的CRL4DCAF1依赖的泛素化降解信号通路活性下调所致。机制层面，过表达PUS10对HSCs的破坏作用并非通过其假尿苷合酶活性实现，而是通过miR139——该microRNA的功能异常会损害HSCs的造血重建能力。一致性实验结果表明，年轻与衰老造血干祖细胞（hematopoietic stem and progenitor cells, HSPCs）的tRNA假尿苷化谱无显著差异，而过表达PUS10可改变HSCs的microRNA表达谱。靶向功能失活Pus10会削弱HSCs的自我更新能力。本研究还对年轻与衰老HSPCs的DM-Ψ-seq数据进行了tRNA假尿苷化谱的比较分析。