Aging-induced pseudouridine synthase 10 impairs hematopoietic stem cells

Yuqian Wang; Zhenzhen Zhang; Hanqing He; Jinghui Song; Yang Cui; Yunan Chen; Yuan Zhuang; Xiaoting Zhang; Mo Li; Xinxiang Zhang; Michael Q Zhang; Minglei Shi; Chengqi Yi; Jianwei Wang

doi:10.3324/haematol.2022.282211

Aging-induced pseudouridine synthase 10 impairs hematopoietic stem cells

Haematologica. 2023 Oct 1;108(10):2677-2689. doi: 10.3324/haematol.2022.282211.

Authors

Yuqian Wang¹, Zhenzhen Zhang², Hanqing He¹, Jinghui Song³, Yang Cui¹, Yunan Chen⁴, Yuan Zhuang⁵, Xiaoting Zhang⁵, Mo Li⁶, Xinxiang Zhang⁴, Michael Q Zhang⁷, Minglei Shi⁸, Chengqi Yi⁹, Jianwei Wang¹⁰

Affiliations

¹ School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084.
² School of Medicine, Tsinghua University, Beijing 100084.
³ Department of Bioengineering, University of California San Diego, La Jolla, CA 92093.
⁴ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing.
⁵ Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing.
⁶ Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191.
⁷ School of Medicine, Tsinghua University, Beijing 100084, China; MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist; Department of Automation, Tsinghua University, Beijing 100084, China; Department of Biological Sciences, Center for Systems Biology, the University of Texas, Richardson, TX 75080-3021. michael.zhang@utdallas.edu.
⁸ School of Medicine, Tsinghua University, Beijing 100084. shiml79@tsinghua.edu.cn.
⁹ Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing. chengqi.yi@pku.edu.cn.
¹⁰ School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084. jianweiwang@mail.tsinghua.edu.cn.

Abstract

Aged hematopoietic stem cells (HSC) exhibit compromised reconstitution capacity and differentiation-bias towards myeloid lineage, however, the molecular mechanism behind it remains not fully understood. In this study, we observed that the expression of pseudouridine (Ψ) synthase 10 is increased in aged hematopoietic stem and progenitor cells (HSPC) and enforced protein of Ψ synthase 10 (PUS10) recapitulates the phenotype of aged HSC, which is not achieved by its Ψ synthase activity. Consistently, we observed no difference of transcribed RNA pseudouridylation profile between young and aged HSPC. No significant alteration of hematopoietic homeostasis and HSC function is observed in young Pus10-/- mice, while aged Pus10-/- mice exhibit mild alteration of hematopoietic homeostasis and HSC function. Moreover, we observed that PUS10 is ubiquitinated by E3 ubiquitin ligase CRL4DCAF1 complex and the increase of PUS10 in aged HSPC is due to aging-declined CRL4DCAF1- mediated ubiquitination degradation signaling. Taken together, this study for the first time evaluated the role of PUS10 in HSC aging and function, and provided a novel insight into HSC rejuvenation and its clinical application.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging
Animals
Hematopoietic Stem Cells / metabolism
Intramolecular Transferases* / genetics
Intramolecular Transferases* / metabolism
Mice
RNA*

Substances

pseudouridine synthases
RNA
Intramolecular Transferases

Grants and funding

Funding: This work was supported by grant numbers Z200022, 82250002, 81870118 and 2018YFA0800200 to JWW, and 2019YFA0110900, 2019YFA0802200 to CQY, and 81890991 to MS from the National Key R&D Program of China or the Beijing Municipal Science & Technology Commission and the National Natural Science Foundation of China.