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FBL catalyzes internal 2′-O-Methylation in mRNA to promote RNA stability

ABSTRACT: 2′-O-Methylation is prominent in ribosome RNA catalyzed by Fibrillarin (FBL). However, the stoichiometry of 2′-O-methylation at base resolution in the internal mRNA and its functions remain to be explored. Here, we firstly investigate the effect of the 2′-O-methylation on the mRNA stability and expression at a genome-wide scale. Combined with Nanopore sequencing and a machine learning strategy, we identified thousands of RNA methylation sites in mRNA and rRNA at base resolution. The mRNA half-life profiling of FBL deficient cells established a direct effect of RNA methylation and FBL binding on the mRNA stability. We further determined the RNA methylation on the expression levels and tested the post-transcriptional effect of elevated FBL mediated 2′-O-Methylation in mRNA within the prostate cancer model. Besides the role of the translational regulation of FBL in rRNA, elevated FBL promotes cancer progress by stabilizing the mRNA through RNA binding and 2′-O-Methylation. Our results reveal a novel mechanism that FBL regulates the 2′-O-methylation and turnover of mRNA at whole transcriptome levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208837 | GEO | 2024/06/20

REPOSITORIES: GEO

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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.

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FBL catalyzes internal 2′-O-Methylation in mRNA to promote RNA stability

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