Dhx38 is required for the maintenance and differentiation of erythro-myeloid progenitors and hematopoietic stem cells by alternative splicing

Jiayi Tu, Shanshan Yu, Jingzhen Li, Mengmeng Ren, Yangjun Zhang, Jiong Luo, Kui Sun, Yuexia Lv, Yunqiao Han, Yuwen Huang, Xiang Ren, Tao Jiang, Zhaohui Tang, Mark Thomas Shaw Williams, Qunwei Lu, Mugen Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations that occur in RNA-splicing machinery may contribute to hematopoiesis-related diseases. How splicing factor mutations perturb hematopoiesis, especially in the differentiation of erythro-myeloid progenitors (EMPs), remains elusive. Dhx38 is a pre-mRNA splicing-related DEAH box RNA helicase, for which the physiological functions and splicing mechanisms during hematopoiesis currently remain unclear. Here, we report that Dhx38 exerts a broad effect on definitive EMPs as well as the differentiation and maintenance of hematopoietic stem and progenitor cells (HSPCs). In dhx38 knockout zebrafish, EMPs and HSPCs were found to be arrested in mitotic prometaphase, accompanied by a ‘grape’ karyotype, owing to the defects in chromosome alignment. Abnormal alternatively spliced genes related to chromosome segregation, the microtubule cytoskeleton, cell cycle kinases and DNA damage were present in the dhx38 mutants. Subsequently, EMPs and HSPCs in dhx38 mutants underwent P53-dependent apoptosis. This study provides novel insights into alternative splicing regulated by Dhx38, a process that plays a crucial role in the proliferation and differentiation of fetal EMPs and HSPCs.
Original languageEnglish
Article numberdev200450
JournalDevelopment (Cambridge, England)
Volume149
Issue number17
Early online date30 Aug 2022
DOIs
Publication statusPublished - Sep 2022

Keywords

  • Splicing factor
  • dhx38
  • Erythro-myeloid progenitors
  • hematopoietic stem and progenitor cells
  • Cell cycle
  • DNA damage

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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