Assistant Professor The Chinese University of Hong Kong (CUHK) Shatin, Hong Kong
Abstract: Fetal hematopoietic stem cells (HSCs) and their committed progenitors (HSPCs) are highly proliferative cells that rely on active ribosome biogenesis to support their rapid expansion during fetal hematopoiesis. Insufficient ribosome biogenesis, a pathological condition known as ribosomopathy, activates the p53 pathway and induces cell cycle arrest in immature progenitor cells, leading to disrupted hematopoiesis and erythroid aplasia (anemia). DDX21 is an RNA helicase that regulates ribosome biogenesis by modulating rRNA splicing, processing, and ribosomal protein transcription. To test whether ribosome insufficiency is a cause of defective hematopoiesis, we generated Ddx21 conditional knockout (Ddx21cKO) in hematopoietic cells using Vav1-Cre;Ddx21f/f mice. The Ddx21cKO embryos showed fetal anemia and regression of the fetal liver. We also observed decreased HSPC numbers and their committed progenitors (CMP, GMP, and MEP) at E13.5 onwards. Terminal differentiation of erythroid cells was unbalanced, with more immature erythroblasts accumulated at basophilic and polychromatic stages. Consistently, E13.5 Ddx21cKO fetal liver cells failed to constitute the blood cells when transplanted into lethally irradiated mice, suggesting that Ddx21 is essential for fetal hematopoiesis. Analysis of the DDX21 protein interactome revealed several histone modification enzymes directly interacting with DDX21. Among them, the histone deacetylases (HDAC1/2) are components of the repressive complex for epigenetic regulation. Interestingly, the loss of Ddx21 in HSPC resulted in the downregulation of ATAC peaks at transcription start site, suggesting a more closed chromatin including the promoters of rDNA tandem repeats. These results suggest that DDX21 may prevent the HDAC complex from improper silencing of genes essential for HSPC proliferation. Our findings reveal a new function of DDX21 in regulating hematopoiesis via an epigenetic mechanism.
Funding Source: This study was supported by a grant from Hong Kong Research Grants Council (RGC) General Research Fund (Project No. 14104321), and a grant from Health@InnoHK Program launched by Innovation Technology Commission, Hong Kong S.A.R. China
