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A PRC2-independent function for EZH2 in regulating rRNA 2′-O methylation and IRES-dependent translation

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143975 | GEO | 2020/12/10

REPOSITORIES: GEO

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A PRC2-independent function for EZH2 in regulating rRNA 2′-O methylation and IRES-dependent translation

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

Effect of rRNA methylation defect on protein composition of human ribosomes

2018-04-09 | PXD007244 | Pride

Transcription profile of FBL-knock down ES cells

Project description:Pluripotent stem cells have been shown to have unique nuclear properties, e.g., hyperdynamic chromatin and large, condensed nucleoli. However, the contribution of the latter unique nucleolar character to pluripotency has not been well understood. Here, we show fibrillarin (FBL), a critical methyltransferase for ribosomal RNA (rRNA) processing in nucleoli, as one of the proteins highly expressed in pluripotent embryonic stem (ES) cells. Stable expression of FBL in ES cells prolonged the pluripotent state of mouse ES cells cultured in the absence of leukemia inhibitory factor (LIF). Analyses using deletion mutants and a point mutant revealed that the methyltransferase activity of FBL regulates stem cell pluripotency. Knock down of this gene led to significant delays in rRNA processing, growth inhibition, and apoptosis in mouse ES cells. Interestingly, both partial knock down of FBL and treatment with actinomycin D, an inhibitor for rRNA synthesis, induced the expression of differentiation markers in the presence of LIF and promoted stem cell differentiation into neuronal lineages. Moreover, we identified p53 signaling as the regulatory pathway for pluripotency and differentiation of ES cells. These results suggest that proper activity of rRNA production in nucleoli is a novel factor for the regulation of pluripotency and differentiation ability of ES cells. Tc-inducible FBL-knock down ES cells were cultured for 2 days with or without Tc in the presence of LIF. These 2 conditions were analysed transcription profile.

2014-08-01 | E-GEOD-51139 | biostudies-arrayexpress

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

Project description: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.

2024-06-20 | GSE208837 | GEO

Transcription profile of FBL-knock down ES cells

2014-08-01 | GSE51139 | GEO

SIRT7-dependent deacetylation of fibrillarin controls H2A methylation and rRNA synthesis during the cell cycle

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

Fibrillarin homologs are required for divergent cell lineage development by translational regulation in planarian homeostasis and regeneration [RiboMeth-Seq]

Project description:Translational regulation in adult regenerative tissue remains unclear. Planarians, renowned for remarkable cell turnover and tissue regeneration capabilities, are regenerative flatworms that provide an ideal model to address the gap in knowledge between translational control and cell turnover during adult tissue homeostasis and regeneration. Fibrillarin (FBL) is an RNA 2-O’-methyltransferase crucial for rRNA processing, playing a pivotal role in translational regulation. We explored this in planarian Schmidtea mediterranea and identified two FBL homologs: Smed-fbl-1 (fbl-1) and Smed-fbl-2 (fbl-2) are essential for homeostasis and regeneration, but have distinct roles. fbl-1 is enriched in neoblasts and essential for multiple progenitor cell differentiation. Conversely, fbl-2 is expressed in egr5+ epidermal progenitors, crucial for late-stage epidermal lineage specification. Knockdown (KD) of fbl-1 and fbl-2 resulted in different 2-O’-methylation patterns, suggesting their influence on specific mRNA translation during regeneration. Riboseq analysis revealed that fbl-1 KD reduced the translation of genes associated with alternative splicing, cell cycle, and DNA replication, while fbl-2 KD reduced the translation of genes related to protein stability. Interestingly, fbl-2+ cells spatially correlated with wnt-1+ cells, hinting at fbl-2’s role in its localization. Our study indicated that duplicate fbl genes may have a compensatory role in the development of specific cell lineages. This finding underscores the significance of rRNA modification in translation regulation during the maintenance and regeneration of adult tissues.

2024-11-13 | GSE255590 | GEO

Fibrillarin homologs are required for divergent cell lineage development by translational regulation in planarian homeostasis and regeneration [Ribo-seq]

2024-11-13 | GSE255594 | GEO

Evidence for rRNA 2'-O-methylation plasticity: control of intrinsic translational capabilities of human ribosomes

Project description:Ribosomal RNAs (rRNAs) are main effectors of mRNA decoding, peptide-bond formation and ribosome dynamics during translation. Ribose 2'-O-methylation (2'-O-Me) is the most abundant rRNA chemical modification, and display a complex pattern in rRNA. 2'-O-Me was shown to be essential for accurate and efficient protein synthesis in eukaryotic cells. However, whether rRNA 2'-O-Me is an adjustable feature of the human ribosome and a means of regulating ribosome function remains to be determined. Here we challenged rRNA 2'-O-Me globally by inhibiting the rRNA methyl-transferase fibrillarin (FBL) in human cells. Using RiboMethSeq, a non-biased quantitative mapping of 2'-O-Me, we identified a repertoire of 2'-O-Me sites subjected to variation and demonstrate that functional domains of ribosomes are targets of 2'-O-Me plasticity. Using the cricket paralysis virus (CrPV) IRES element, as a model, coupled to in vitro translation, we show that the intrinsic capability of ribosomes to translate mRNAs is modulated through 2'-O-Me pattern and not by non-ribosomal actors of the translational machinery. Our results establish rRNA 2'-O-methylation plasticity as a mechanism providing functional specificity to human ribosomes.

2018-01-19 | GSE105248 | GEO

p26 condensates from Pea enation mosaic virus 2 sequester ribosomal components and suppress translation

Project description:The p26 movement protein of Pea enation mosaic virus 2 (PEMV2) interacts with the 2'-O-methyltransferase fibrillarin within nuclear and cytoplasmic condensates. This study analyzed global 2'-O-methylation patterns in PEMV2-infected Nicotiana benthamiana using RiboMethSeq, focusing on ribosomal RNAs (rRNAs). The aim was to assess whether PEMV2 disrupts rRNA 2'-O-methylation to interfere with host translation or ribosome assembly.

2024-11-18 | GSE275487 | GEO

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