SNORD113-114 cluster maintains hematopoietic stem cell self-renewal via orchestrating the translation machinery
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ABSTRACT:
PROVIDER: PRJNA1129072 | ENA |
REPOSITORIES: ENA
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Project description: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.
2024-10-30 | GSE270936 | GEO
Project description:SNORD113-114 cluster regulates self-renewal of hematopoietic stem cells via orchestrating the translation machinery
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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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2021-12-05 | GSE189988 | GEO
Project description:Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.
2023-03-11 | PXD032277 | Pride