The dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia [ribosome profiling]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE185489 | GEO | 2022/11/23
REPOSITORIES: GEO
Similar Datasets
Project description:We investigated the effect of FBL and SNRD127 on rRNA 2'-O-Me in human leukemai cell Kasumi-1.
2022-11-23 | GSE184724 | GEO
Project description:Eukaryotic ribosomal RNA carries diverse posttranscriptional modifications, the function of which are mostly unexplored. The evolutionarily conserved 2’-O-methylation (2’-O-Me) occurs at more than 100 sites and is essential for ribosome biogenesis. Plasticity of 2´-O-Me in ribosomes and its functional consequences in human disease remain to be elucidated. The effect of rRNA 2’-O-Me on protein translation was investigated by nascent proteomcis analysis coupled with RNA-Seq in human leukemia cell line Kasumi-1 with and without knockdown of 2´-O-methyltransferase FBL.
2022-11-23 | GSE184721 | GEO
Project description:Eukaryotic ribosomal RNA carries diverse posttranscriptional modifications, among which the evolutionarily conserved 2’-O-methylation (2’-O-Me) occurs at more than 100 sites and is essential for ribosome biogenesis. Plasticity of 2´-O-Me in ribosomes and its functional consequences in human disease are not yet known. Here, we present the full rRNA 2’-O-Me landscape (ribomethylome) of human acute myeloid leukemia (AML) through profiling 94 patient samples as well as 21 normal hematopoietic samples of 5 different lineages. While interior modification sites in functional centers are persistently fully 2’-O-methylated in human AMLs, methylation on ribosome exterior sites is unprecedentedly dynamic. Higher 2’-O-methylation on exterior dynamic sites is associated with leukemia stem cell (LSC) signatures. Forced expression of enzymatically active but not of the catalytic defect 2’-O-methyltransferase FBL induces AML stemness and accelerates leukemogenesis in patient-derived xenografts. Mechanistically, ribomethylome dynamics shifted mRNA ribosome translation preferences. High rRNA 2’-O-Me enhances translation of amino acid transporters enriched in optimal codons and subsequently increases intra-cellular amino acid levels. Methylation on a single exterior modification site affects leukemia stem cell activity. The Guanosine 1447 on the small subunit ribosomal RNA is the most variable site in primary AMLs. Gm1447 is increased in leukemia stem cell populations compared to non-leukemogenic blast cells and AML specimens with higher Gm1447 are enriched for leukemia stem cell genes. Comparison of Gm1447high and Gm1447low ribosome structure solved by cryo-electron microscopy demonstrated disassociation of LYAR from Gm1447low ribosomes. Suppression of Gm1447 alone is sufficient to suppress translation of amino acid transporters, resulting in decreased cellular amino acid levels and leukemia stem cell activity. Taken together, our data reveal the dynamic FBL-mediated rRNA 2'-O-Me landscape as a novel epitranscriptomic level of control employed by leukemic stem cells and may enable new strategies to target human AML.
2023-03-11 | PXD029527 | Pride
Project description:Eukaryotic ribosomal RNA carries diverse posttranscriptional modifications, the function of which are mostly unexplored. The evolutionarily conserved 2’-O-methylation (2’-O-Me) occurs at more than 100 sites and is essential for ribosome biogenesis. Plasticity of 2´-O-Me in ribosomes and its functional consequences in human disease remain to be elucidated. We performed RiboMethSeq to estabolish the full rRNA 2’-O-Me landscape (ribomethylome) in human acute myeloid leukemia (AML) through profiling 94 patient samples as well as 21 normal hematopoietic samples of 5 different lineages. The gene expression in the same samples was determined by RNA-Seq. We found that higher 2’-O-methylation on exterior dynamic sites associated with leukemia stem cell (LSC) signatures.
2022-11-23 | GSE184722 | GEO
Project description:Eukaryotic ribosomal RNA carries diverse posttranscriptional modifications, the function of which are mostly unexplored. The evolutionarily conserved 2’-O-methylation (2’-O-Me) occurs at more than 100 sites and is essential for ribosome biogenesis. Plasticity of 2´-O-Me in ribosomes and its functional consequences in human disease remain to be elucidated. We performed RiboMethSeq to estabolish the full rRNA 2’-O-Me landscape (ribomethylome) in human acute myeloid leukemia (AML) through profiling 94 patient samples as well as 21 normal hematopoietic samples of 5 different lineages. The gene expression in the same samples was determined by RNA-Seq. We found that higher 2’-O-methylation on exterior dynamic sites associated with leukemia stem cell (LSC) signatures.
2022-11-23 | GSE184727 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-11-23 | GSE184728 | GEO
Project description:Ribosomal RNAs (rRNAs) are main effectors of mRNA decoding, peptide-bond formation and ribosome dynamics during translation. Ribose 2'-O-methylation is the most abundant rRNA chemical modification, and display a complex pattern in rRNA. We globally challenged rRNA 2'-O-Me by inhibiting the rRNA methyl-transferase fibrillarin (FBL) in human cells. Since FBL participates in rRNA processing, we wonder if FBL knockdown could alter the assembly of ribosomes.
2018-04-09 | PXD007244 | Pride
Project description:Overactivated ribosome biogenesis is a common feature of cancer. However, the underlying molecular mechanism remains elusive. Herein, we report enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, could interact with fibrillarin (FBL) directly in the nucleolus. While loss of EZH2 does not impact FBL-mediated histone H2AQ104 methylation (H2AQ104me) and 18S rRNA processing, EZH2 is proved to be involved in rRNA 2′-O methylation in a manner dependent of its interaction with FBL. Mechanistically, EZH2 strengthens the fibrillarin (FBL)-NOP56 interaction by binding to both proteins and thus facilitates the assembly of box C/D small nucleolar ribonucleoprotein (box C/D snoRNP). Strikingly, EZH2 deficiency alters translational efficiency and reduces internal ribosome entry site (IRES) activity of key oncogenes in prostate cancer. In summary, our findings reveal a novel non-methyltransferase role of EZH2 that mediates FBL functions, which may provide more options for the development of EZH2-targeting curative strategies in cancer.
2020-12-10 | GSE159004 | GEO
Project description:Overactivated ribosome biogenesis is a common feature of cancer. However, the underlying molecular mechanism remains elusive. Herein, we report enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, could interact with fibrillarin (FBL) directly in the nucleolus. While loss of EZH2 does not impact FBL-mediated histone H2AQ104 methylation (H2AQ104me) and 18S rRNA processing, EZH2 is proved to be involved in rRNA 2′-O methylation in a manner dependent of its interaction with FBL. Mechanistically, EZH2 strengthens the fibrillarin (FBL)-NOP56 interaction by binding to both proteins and thus facilitates the assembly of box C/D small nucleolar ribonucleoprotein (box C/D snoRNP). Strikingly, EZH2 deficiency alters translational efficiency and reduces internal ribosome entry site (IRES) activity of key oncogenes in prostate cancer. In summary, our findings reveal a novel non-methyltransferase role of EZH2 that mediates FBL functions, which may provide more options for the development of EZH2-targeting curative strategies in cancer.
2020-12-10 | GSE143975 | GEO
Project description:Fibrillarin (FBL) is a dual function nucleolar protein which catalyses 2´-O methylation of pre-rRNA and methylation of histone H2A at glutamine 104 (H2AQ104me). The mechanisms that regulate FBL activity are unexplored. Here we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7. While reversible acetylation does not impact FBL-mediated pre-rRNA methylation, hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromsing H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. At the onset of mitosis, nucleolar disassembly is accompanied by hyperacetylation of FBL, loss of H2AQ104me and repression of Pol I transcription. H2AQ104me and transcriptional activity are restored by overexpression of an acetylation-deficient but not by an acetylation-mimicking FBL mutant. The results reveal that SIRT7-dependent deacetylation impacts nucleolar activity by a FBL-driven circuitry that mediates cell cycle-dependent fluctuation of rDNA transcription.
2018-12-12 | GSE115360 | GEO