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SNORD113-114 cluster maintains hematopoietic stem cell self-renewal via orchestrating the translation machinery

ABSTRACT: Hematopoietic stem cells (HSCs) self-renew and differentiate to replenish the pool of blood cells, which require a low but finely-tuned protein synthesis rate. Nonetheless, the translatome landscape in HSCs and how the translation machinery influences HSC self-renewal remain largely elusive. Here, we perform the ultra-low-input Ribo-seq in HSCs, progenitor and lineage cells, and reveal HSCs specifically translated genes involved in rRNA processing. We then systematically profiled the snoRNAs and uncover an indispensable role of SNORD113-114 cluster at the Dlk1-Gtl2 imprinting locus in regulating HSC self-renewal. Maternal knockout of this cluster (Mat-KO) significantly impairs HSC self-renewal, while loss of the paternal allele shows no obvious phenotype. Mechanistically, Mat-KO results in dysregulation of translation machinery (rRNA 2’-O-Me modifications, pre-rRNA processing, 60S ribosome assembly, and translation) and induces nucleolar stress in HSCs, which exempts p53 from MDM2 mediated proteasomal degradation and eventually leads to apoptosis. Finally, overexpression of snoRNAs or L-leucine mediated translation recovery rescues deficiency in Mat-KO HSCs. Collectively, our study provides a new facet to our understanding of snoRNA-mediated regulation in HSC homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE270936 | GEO | 2024/10/30

REPOSITORIES: GEO

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Project description:Hematopoietic stem cells (HSCs) play a crucial role in maintaining the steady supply of blood cells throughout an organism’s lifetime. Understanding the regulatory mechanisms governing HSC homeostasis is of particular importance for regenerative medicine and stem cell-based therapies. Translatome refers to the ensemble mRNA transcripts being actively translated on ribosomes within a cell type, under specific physio/pathological conditions. Translatome profiling provides insights into the regulation of gene expression at the translational level, going beyond traditional transcriptome analysis. In this study, we systematically profiled the translatome landscapes of hematopoietic cells, and unraveled novel insights on HSC functionality and regulation mechanisms. Moreover, for further exploring underlying regulation mechanisms of translatome, we systematically screened the snoRNAs in hematopoietic cells and uncovered an indispensable role for the maternally expressed snoRNA cluster SNORD113-114 at the Dlk1-Gtl2 imprinting region in regulation of HSC self-renewal. Maternal knockout of this cluster (Mat-KO) significantly impaired HSC self-renewal, while loss of the paternal allele caused no obvious abnormal hematological phenotype. Mechanistically, Mat-KO resulted in dysregulation of translation machinery, in terms of 2’-O-Me modifications on rRNAs, rRNA processing, ribosome function and translatome. Finally, Loss of SNORD113-114 cluster induced impaired ribosome biogenesis checkpoint/nucleolar stress in HSCs, which exempted p53 from proteasomal degradation and eventually led to apoptosis in HSCs. Collectively, our findings shed light on the intricate molecular mechanisms governing HSC behavior and provide potential therapeutic targets for enhancing HSC function and advancing regenerative medicine. Understanding the translation regulation of gene expression in HSCs has significant implications for stem cell biology and offers promising avenues for clinical applications.

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SNORD113-114 cluster maintains hematopoietic stem cell self-renewal via orchestrating the translation machinery

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