Identification of an RNA-binding region in 18S dimethyladenosine methyltransferase DIMT1 essential for proliferation of acute myeloid leukemia cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197276 | GEO | 2024/04/09
REPOSITORIES: GEO
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Project description:The nucleolus composes hundreds of proteins that play distinct roles in ribosomal RNA (rRNA) processing within Fibrillar Center/Dense Fibrillar Component (FC/DFC) units and ribosome assembly in Granular Component (GC). The sub-nucleolar localization of most proteins and how their unique localization facilitates rRNA processing have remained elusive. By screening 200 nucleolar candidate proteins with high-resolution, live-cell microscopy, we identified a previously undescribed sub-nucleolar compartment, named the periphery of DFC (PDFC). Among the 12 proteins identified in PDFC, URB1 (unhealthy ribosome biogenesis 1) is required for PDFC organization and proper 3' end processing of 47S pre-rRNA. URB1 binds between the 28S rRNA and the 3' external transcribed spacer (3' ETS) to ensure 3' ETS removal, which occurs at the DFC/PDFC boundary. Loss of URB1 leads to accumulation of aberrant 3' ETS-retained 32S pre-rRNA variants, which activates exosome-dependent nucleolar surveillance. This causes decreased 28S rRNA production, reduced cell proliferation and retarded mouse embryonic pre-implementation development. Furthermore, urb1 depletion results in developmental craniofacial disorder in zebrafish, which can be at least partially rescued by further depleting exosome components. Together, this study provides new insights into functional sub-nucleolar organizations, identifies a physiologically essential step in rRNA maturation and emphasizes the exosome-dependent pre-rRNA surveillance pathway.
2023-01-04 | GSE196625 | GEO
Project description:The nucleolus composes hundreds of proteins that play distinct roles in ribosomal RNA (rRNA) processing within Fibrillar Center/Dense Fibrillar Component (FC/DFC) units and ribosome assembly in Granular Component (GC). The sub-nucleolar localization of most proteins and how their unique localization facilitates rRNA processing have remained elusive. By screening 200 nucleolar candidate proteins with high-resolution, live-cell microscopy, we identified a previously undescribed sub-nucleolar compartment, named the periphery of DFC (PDFC). Among the 12 proteins identified in PDFC, URB1 (unhealthy ribosome biogenesis 1) is required for PDFC organization and proper 3' end processing of 47S pre-rRNA. URB1 binds between the 28S rRNA and the 3' external transcribed spacer (3' ETS) to ensure 3' ETS removal, which occurs at the DFC/PDFC boundary. Loss of URB1 leads to accumulation of aberrant 3' ETS-retained 32S pre-rRNA variants, which activates exosome-dependent nucleolar surveillance. This causes decreased 28S rRNA production, reduced cell proliferation and retarded mouse embryonic pre-implementation development. Furthermore, urb1 depletion results in developmental craniofacial disorder in zebrafish, which can be at least partially rescued by further depleting exosome components. Together, this study provides new insights into functional sub-nucleolar organizations, identifies a physiologically essential step in rRNA maturation and emphasizes the exosome-dependent pre-rRNA surveillance pathway.
2023-01-04 | GSE194413 | GEO
Project description:Ribosome biosynthesis plays a crucial role in regulating protein translation and is essential for cell growth and development in physiological progress. The progression and recurrence of Pterygia mainly occur due to the abnormal proliferation and migration of stromal Pterygia fibroblasts. Small nucleolar RNA U3 (U3 snoRNA), harboring the atypical C/D boxes, is involved in 18S ribosomal RNA (18S rRNA) synthesis; however, the mechanism of U3 snoRNA in Pterygia remains unclear. Methods: Primary HCFs and HPFs were separated and cultured from fresh conjunctival grafts and Pterygia tissues. The PLKO.1 lentiviral system and CRISPR/Cas9 recombinant construct were, respectively, used to overexpress and silence U3 snoRNA in HPF and HCF cells for further specific phenotypes analysis. RNA-seq and TMT-labeled quantitative protein mass spectrometry were utilized to evaluate the effect of U3 snoRNA on mRNA transcripts and protein synthesis. Results: Reduced U3 snoRNA in Pterygia promotes HCF or HPF cells' proliferation, migration, and cell cycle but has no significant effect on apoptosis. U3 snoRNA modulates 18S rRNA synthesis through shearing precursor ribosomal RNA 47S rRNA at the 5′ external transcribed spacer (5′ ETS). Moreover, the altered U3 snoRNA causes mRNA and protein differential expression in HCF or HPF cells. Conclusion: The atypical U3 snoRNA regulates the translation of specific proteins to exert a suppressive function in Pterygia through modulating the 18S RNA synthesis. Here, we uncover a novel insight into U3 snoRNA biology in the development of Pterygia.
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Project description:Approximately one third of acute myeloid leukemias (AMLs) are characterized by aberrant cytoplasmic localization of Nucleophosmin (NPMc+ AML), consequent to mutations in the NPM putative nucleolar localization signal. These events are mutually exclusive with the major AML-associated chromosomal rearrangements, and are frequently associated with normal karyotype, Fms-like tyrosine kinase (FLT3) mutations and multilineage involvement. We report the gene expression profiles of 78 de novo AMLs (72 with normal karyotype; 6 with non-major chromosomal abnormalities) that were characterized for the subcellular localization and mutation status of NPM. Unsupervised clustering clearly separated NPMc+ from NPMc- AMLs, regardless of the presence of FLT3 mutations or non-major chromosomal rearrangements, supporting the concept that NPMc+ AML represents a distinct entity. The molecular signature of NPMc+ AML includes up-regulation of several genes putatively involved in the maintenance of a stem cell phenotype, suggesting that NPMc+ AML may derive from a multipotent hematopoietic progenitor. 78 de novo AMLs, negative for AML-associated chromosomal translocations at the cytogenetic and/or molecular level.
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Project description:Nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. Its role in regulating stem cell fate is unclear. Here, we present multiple lines of evidence that nucleolar stress induced by interfering rRNA biogenesis can drive two-cell stage embryo-like (2C-like) transcriptional program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, the liquid-liquid phase separation (LLPS) mediated by rRNA and nucleolar proteins maintains the formation of peri-nucleolar heterochromatin (PNH). When mES cells undergo rRNA biogenesis defect, the normal LLPS of nucleolus is disrupted, causing deconjugation of NCL/TRIM28 complex on PNH and changes of epigenetic state and 3D structure of PNH, which leads to Dux, a conserved multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals, to be released from the PNH region, activation of 2C-like program and transition of mES cells to 2C-like cells. Embryos with rRNA biogenesis defect are incompatible to develop from 2-cell (2C) to blastocyte (BC) and appear to skew from the blastocyst to earlier cleavage embryo signatures. Our results highlight that nucleolar LLPS-mediated 3D chromatin structure reshaping of PNH compartment regulates the fate transition of mES cells to 2C-like cells. Our findings for the first time elucidate the novel roles of rRNA biogenesis in regulating the 2C-like and ES state homeostasis in cultured cells and suggest that rRNA biogenesis is a new molecular switch from nucleolus-unmatured 2C stage to nucleolus-matured BC stage during murine pre-implantation embryo development.
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Project description:Nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. Its role in regulating stem cell fate is unclear. Here, we present multiple lines of evidence that nucleolar stress induced by interfering rRNA biogenesis can drive two-cell stage embryo-like (2C-like) transcriptional program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, the liquid-liquid phase separation (LLPS) mediated by rRNA and nucleolar proteins maintains the formation of peri-nucleolar heterochromatin (PNH). When mES cells undergo rRNA biogenesis defect, the normal LLPS of nucleolus is disrupted, causing deconjugation of NCL/TRIM28 complex on PNH and changes of epigenetic state and 3D structure of PNH, which leads to Dux, a conserved multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals, to be released from the PNH region, activation of 2C-like program and transition of mES cells to 2C-like cells. Embryos with rRNA biogenesis defect are incompatible to develop from 2-cell (2C) to blastocyte (BC) and appear to skew from the blastocyst to earlier cleavage embryo signatures. Our results highlight that nucleolar LLPS-mediated 3D chromatin structure reshaping of PNH compartment regulates the fate transition of mES cells to 2C-like cells. Our findings for the first time elucidate the novel roles of rRNA biogenesis in regulating the 2C-like and ES state homeostasis in cultured cells and suggest that rRNA biogenesis is a new molecular switch from nucleolus-unmatured 2C stage to nucleolus-matured BC stage during murine pre-implantation embryo development.
2021-09-15 | GSE166027 | GEO
Project description:Nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. Its role in regulating stem cell fate is unclear. Here, we present multiple lines of evidence that nucleolar stress induced by interfering rRNA biogenesis can drive two-cell stage embryo-like (2C-like) transcriptional program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, the liquid-liquid phase separation (LLPS) mediated by rRNA and nucleolar proteins maintains the formation of peri-nucleolar heterochromatin (PNH). When mES cells undergo rRNA biogenesis defect, the normal LLPS of nucleolus is disrupted, causing deconjugation of NCL/TRIM28 complex on PNH and changes of epigenetic state and 3D structure of PNH, which leads to Dux, a conserved multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals, to be released from the PNH region, activation of 2C-like program and transition of mES cells to 2C-like cells. Embryos with rRNA biogenesis defect are incompatible to develop from 2-cell (2C) to blastocyte (BC) and appear to skew from the blastocyst to earlier cleavage embryo signatures. Our results highlight that nucleolar LLPS-mediated 3D chromatin structure reshaping of PNH compartment regulates the fate transition of mES cells to 2C-like cells. Our findings for the first time elucidate the novel roles of rRNA biogenesis in regulating the 2C-like and ES state homeostasis in cultured cells and suggest that rRNA biogenesis is a new molecular switch from nucleolus-unmatured 2C stage to nucleolus-matured BC stage during murine pre-implantation embryo development.
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Project description:Nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. Its role in regulating stem cell fate is unclear. Here, we present multiple lines of evidence that nucleolar stress induced by interfering rRNA biogenesis can drive two-cell stage embryo-like (2C-like) transcriptional program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, the liquid-liquid phase separation (LLPS) mediated by rRNA and nucleolar proteins maintains the formation of peri-nucleolar heterochromatin (PNH). When mES cells undergo rRNA biogenesis defect, the normal LLPS of nucleolus is disrupted, causing deconjugation of NCL/TRIM28 complex on PNH and changes of epigenetic state and 3D structure of PNH, which leads to Dux, a conserved multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals, to be released from the PNH region, activation of 2C-like program and transition of mES cells to 2C-like cells. Embryos with rRNA biogenesis defect are incompatible to develop from 2-cell (2C) to blastocyte (BC) and appear to skew from the blastocyst to earlier cleavage embryo signatures. Our results highlight that nucleolar LLPS-mediated 3D chromatin structure reshaping of PNH compartment regulates the fate transition of mES cells to 2C-like cells. Our findings for the first time elucidate the novel roles of rRNA biogenesis in regulating the 2C-like and ES state homeostasis in cultured cells and suggest that rRNA biogenesis is a new molecular switch from nucleolus-unmatured 2C stage to nucleolus-matured BC stage during murine pre-implantation embryo development.
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Project description:Nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. Its role in regulating stem cell fate is unclear. Here, we present multiple lines of evidence that nucleolar stress induced by interfering rRNA biogenesis can drive two-cell stage embryo-like (2C-like) transcriptional program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, the liquid-liquid phase separation (LLPS) mediated by rRNA and nucleolar proteins maintains the formation of peri-nucleolar heterochromatin (PNH). When mES cells undergo rRNA biogenesis defect, the normal LLPS of nucleolus is disrupted, causing deconjugation of NCL/TRIM28 complex on PNH and changes of epigenetic state and 3D structure of PNH, which leads to Dux, a conserved multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals, to be released from the PNH region, activation of 2C-like program and transition of mES cells to 2C-like cells. Embryos with rRNA biogenesis defect are incompatible to develop from 2-cell (2C) to blastocyte (BC) and appear to skew from the blastocyst to earlier cleavage embryo signatures. Our results highlight that nucleolar LLPS-mediated 3D chromatin structure reshaping of PNH compartment regulates the fate transition of mES cells to 2C-like cells. Our findings for the first time elucidate the novel roles of rRNA biogenesis in regulating the 2C-like and ES state homeostasis in cultured cells and suggest that rRNA biogenesis is a new molecular switch from nucleolus-unmatured 2C stage to nucleolus-matured BC stage during murine pre-implantation embryo development.
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Project description:The transcription factor BMAL1 is a core element of the circadian clock that contributes to cyclic control of genes transcribed by RNA polymerase II. By using biochemical cellular fractionation and immunofluorescence analyses we reveal a previously uncharacterized nucleolar localization for BMAL1. We used an unbiased approach to determine the BMAL1 interactome by mass spectrometry and identified NOP58 as a prominent nucleolar interactor. NOP58, a core component of the box C/D small nucleolar ribonucleoprotein complex, associates with Snord118 to control specific pre-ribosomal RNA (rRNA) processing steps. These results suggest a non-canonical role of BMAL1 in rRNA regulation. Indeed, we show that BMAL1 controls NOP58-associated Snord118 nucleolar levels and cleavage of unique pre-rRNA intermediates. Our findings identify an unsuspected function of BMAL1 in the nucleolus that appears distinct from its canonical role in the circadian clock system
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