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

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.