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1
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Ramirez C, Perenthaler E, Lauria F, Tebaldi T, Viero G. Computational limitations and future needs to unravel the full potential of 2'-O-Methylation and C/D box snoRNAs. RNA Biol 2025. [PMID: 40377202 DOI: 10.1080/15476286.2025.2506712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 05/05/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025] Open
Abstract
This review evaluates the current state of C/D snoRNA databases and prediction tools in relation to 2'-O-methylation (2'-O-Me). It highlights the limitations of existing resources in accurately annotating and predicting guide snoRNAs, particularly for newly identified 2"-O-Me sites. We emphasize the need for advanced computational approaches specifically tailored to 2"-O-Me to enable the discovery and functional analysis of snoRNAs. Given the growing importance of 2'-O-Me in areas such as cancer epitranscriptomics, ribosome biogenesis, and heterogeneity, existing tools remain inadequate. As 2'-O-Me gains recognition as a potential biomarker and therapeutic target, more sophisticated methods are urgently needed to improve snoRNA annotation and prediction, facilitating biomedical advancements.
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Affiliation(s)
- Christian Ramirez
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | | | | | - Toma Tebaldi
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy
- Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA
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2
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Chao YL, Zhou KI, Forbes KK, Porrello A, Gentile GM, Zhu Y, Chack AC, John Mary DJS, Liu H, Cockman E, Edatt L, Goda GA, Zhao JJ, Abou Assi H, Wiedner HJ, Tsai Y, Wilkinson L, Van Swearingen AED, Carey LA, Giudice J, Dominguez D, Holley CL, Pecot CV. Snord67 promotes breast cancer metastasis by guiding U6 modification and modulating the splicing landscape. Nat Commun 2025; 16:4118. [PMID: 40316533 PMCID: PMC12048515 DOI: 10.1038/s41467-025-59406-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 04/22/2025] [Indexed: 05/04/2025] Open
Abstract
Previously considered "housekeeping" genes, small nucleolar RNAs (snoRNAs) are increasingly understood to have wide-ranging functions in cancer, yet their role in metastasis has been less well studied. Here, we identify the snoRNA Snord67 as a regulator of lymph node (LN) metastasis in breast cancer. Snord67 expression is enriched in LN metastases in an immune-competent mouse model of female breast cancer. In an orthotopic breast cancer model, loss of Snord67 decreases LN metastasis. In a model of lymphatic metastasis, Snord67 loss decreases LN tumor growth and distant metastases. In breast cancer cell lines, Snord67 knockout results in loss of targeted 2'-O-methylation on U6 small nuclear RNA, as well as widespread changes in splicing. Together, these results demonstrate that Snord67 regulates splicing and promotes the growth of LN metastases and subsequent spread to distant metastases. SnoRNA-guided modifications of the spliceosome and regulation of splicing may represent a potentially targetable pathway in cancer.
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Affiliation(s)
- Yvonne L Chao
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Hematology & Oncology, University of Pittsburgh, Pittsburgh, PA, USA
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA
- VA Pittsburgh Health System, Pittsburgh, PA, USA
| | - Katherine I Zhou
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kwame K Forbes
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alessandro Porrello
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Gabrielle M Gentile
- Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Curriculum in Genetics and Molecular Biology (GMB), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yinzhou Zhu
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Aaron C Chack
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Curriculum in Genetics and Molecular Biology (GMB), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Dixcy J S John Mary
- Division of Hematology & Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Haizhou Liu
- Division of Hematology & Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Eric Cockman
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Lincy Edatt
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Grant A Goda
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Justin J Zhao
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Hala Abou Assi
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Hannah J Wiedner
- Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Curriculum in Genetics and Molecular Biology (GMB), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yihsuan Tsai
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
| | - Lily Wilkinson
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
| | | | - Lisa A Carey
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
- Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jimena Giudice
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Curriculum in Genetics and Molecular Biology (GMB), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Daniel Dominguez
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Christopher L Holley
- Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
| | - Chad V Pecot
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
- Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- UNC RNA Discovery Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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3
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Jouravleva K, Zamore PD. A guide to the biogenesis and functions of endogenous small non-coding RNAs in animals. Nat Rev Mol Cell Biol 2025; 26:347-370. [PMID: 39856370 DOI: 10.1038/s41580-024-00818-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2024] [Indexed: 01/27/2025]
Abstract
Small non-coding RNAs can be categorized into two main classes: structural RNAs and regulatory RNAs. Structural RNAs, which are abundant and ubiquitously expressed, have essential roles in the maturation of pre-mRNAs, modification of rRNAs and the translation of coding transcripts. By contrast, regulatory RNAs are often expressed in a developmental-specific, tissue-specific or cell-type-specific manner and exert precise control over gene expression. Reductions in cost and improvements in the accuracy of high-throughput RNA sequencing have led to the identification of many new small RNA species. In this Review, we provide a broad discussion of the genomic origins, biogenesis and functions of structural small RNAs, including tRNAs, small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), vault RNAs (vtRNAs) and Y RNAs as well as their derived RNA fragments, and of regulatory small RNAs, such as microRNAs (miRNAs), endogenous small interfering RNAs (siRNAs) and PIWI-interacting RNAs (piRNAs), in animals.
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Affiliation(s)
- Karina Jouravleva
- Laboratoire de Biologie et Modélisation de la Cellule, École Normale Supérieure de Lyon, CNRS UMR5239, Inserm U1293, Université Claude Bernard Lyon 1, Lyon, France.
| | - Phillip D Zamore
- RNA Therapeutics Institute and Howard Hughes Medical Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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4
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Holmes TL, Chabronova A, Denning C, James V, Peffers MJ, Smith JGW. Footprints in the Sno: investigating the cellular and molecular mechanisms of SNORD116. Open Biol 2025; 15:240371. [PMID: 40101781 PMCID: PMC11919532 DOI: 10.1098/rsob.240371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/11/2025] [Accepted: 02/04/2025] [Indexed: 03/20/2025] Open
Abstract
The small nucleolar RNA (snoRNA) SNORD116 is a small non-coding RNA of interest across multiple biomedical fields of research. Much of the investigation into SNORD116 has been undertaken in the context of the congenital disease Prader-Willi syndrome, wherein SNORD116 expression is lost. However, emerging evidence indicates wider roles in various disease and tissue contexts such as cellular growth, metabolism and signalling. Nevertheless, a conclusive mechanism of action for SNORD116 remains to be established. Here, we review the key findings from these investigations, with the aim of identifying common elements from which to elucidate potential targets and mechanisms of SNORD116. A key recurring element identified is disruption to the insulin/IGF-1 and PI3K/mTOR signalling pathways, contributing to many of the phenotypes associated with SNORD116 modulation explored in this review.
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Affiliation(s)
- Terri L. Holmes
- Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich, NorfolkNR4 7UQ, UK
| | - Alzbeta Chabronova
- Department of Musculoskeletal Ageing Science, University of Liverpool, Liverpool, UK
| | - Chris Denning
- Department of Stem Cell Biology, University of Nottingham, Nottingham, UK
| | - Victoria James
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK
| | - Mandy J. Peffers
- Department of Musculoskeletal Ageing Science, University of Liverpool, Liverpool, UK
| | - James G. W. Smith
- Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich, NorfolkNR4 7UQ, UK
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5
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Hamar R, Varga M. The zebrafish ( Danio rerio) snoRNAome. NAR Genom Bioinform 2025; 7:lqaf013. [PMID: 40046902 PMCID: PMC11880993 DOI: 10.1093/nargab/lqaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 02/08/2025] [Accepted: 02/14/2025] [Indexed: 04/16/2025] Open
Abstract
Small nucleolar RNAs (snoRNAs) are one of the most abundant and evolutionary ancient group of functional non-coding RNAs. They were originally described as guides of post-transcriptional rRNA modifications, but emerging evidence suggests that snoRNAs fulfil an impressive variety of cellular functions. To reveal the true complexity of snoRNA-dependent functions, we need to catalogue first the complete repertoire of snoRNAs in a given cellular context. While the systematic mapping and characterization of "snoRNAomes" for some species have been described recently, this has not been done hitherto for the zebrafish (Danio rerio). Using size-fractionated RNA sequencing data from adult zebrafish tissues, we created an interactive "snoRNAome" database for this species. Our custom-designed analysis pipeline allowed us to identify with high-confidence 67 previously unannotated snoRNAs in the zebrafish genome, resulting in the most complete set of snoRNAs to date in this species. Reanalyzing multiple previously published datasets, we also provide evidence for the dynamic expression of some snoRNAs during the early stages of zebrafish development and tissue-specific expression patterns for others in adults. To facilitate further investigations into the functions of snoRNAs in zebrafish, we created a novel interactive database, snoDanio, which can be used to explore small RNA expression from transcriptomic data.
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Affiliation(s)
- Renáta Hamar
- Department of Genetics, ELTE Eötvös Loránd University, Budapest, 1117, Hungary
| | - Máté Varga
- Department of Genetics, ELTE Eötvös Loránd University, Budapest, 1117, Hungary
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6
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Salles J, Lin R, Turecki G. Small Nucleolar RNAs and the Brain: Growing Evidence Supporting Their Role in Psychiatric Disorders. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2025; 5:100415. [PMID: 39867567 PMCID: PMC11758842 DOI: 10.1016/j.bpsgos.2024.100415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 10/20/2024] [Accepted: 10/28/2024] [Indexed: 01/28/2025] Open
Abstract
Noncoding RNAs comprise most of the transcriptome and represent an emerging area of research. Among them, small nucleolar RNAs (snoRNAs) have emerged as a promising target because they have been associated with the development and evolution of several diseases, including psychiatric disorders. snoRNAs are expressed in the brain, with some showing brain-specific expression that indicates specific roles in brain development, function, and dysfunction. However, the role of snoRNAs in conditions that affect the brain needs further investigation to be better understood. This scoping review summarizes existing literature on studies that have investigated snoRNAs in psychiatry and offers insight into potential pathophysiological mechanisms to be further investigated in future research.
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Affiliation(s)
- Juliette Salles
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
| | - Rixing Lin
- Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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7
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Song Z, Bae B, Schnabl S, Yuan F, De Zoysa T, Akinyi MV, Le Roux CA, Choquet K, Whipple AJ, Van Nostrand EL. Mapping snoRNA-target RNA interactions in an RNA-binding protein-dependent manner with chimeric eCLIP. Genome Biol 2025; 26:39. [PMID: 40001124 PMCID: PMC11863803 DOI: 10.1186/s13059-025-03508-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Small nucleolar RNAs (snoRNAs) are non-coding RNAs that function in ribosome and spliceosome biogenesis, primarily by guiding modifying enzymes to specific sites on ribosomal RNA (rRNA) and spliceosomal RNA (snRNA). However, many orphan snoRNAs remain uncharacterized, with unidentified or unvalidated targets, and studies on additional snoRNA-associated proteins are limited. RESULTS We adapted an enhanced chimeric eCLIP approach to comprehensively profile snoRNA-target RNA interactions using both core and accessory snoRNA-binding proteins as baits. Using core snoRNA-binding proteins, we confirmed most annotated snoRNA-rRNA and snoRNA-snRNA interactions in mouse and human cell lines and called novel, high-confidence interactions for orphan snoRNAs. While some of these interactions result in chemical modification, others may have modification-independent functions. We showed that snoRNA ribonucleoprotein complexes containing certain accessory proteins, like WDR43 and NOLC1, enriched for specific subsets of snoRNA-target RNA interactions with distinct roles in ribosome and spliceosome biogenesis. Notably, we discovered that SNORD89 guides 2'-O-methylation at two neighboring sites in U2 snRNA that fine-tune splice site recognition. CONCLUSIONS Chimeric eCLIP of snoRNA-associating proteins enables a comprehensive framework for studying snoRNA-target interactions in an RNA-binding protein-dependent manner, revealing novel interactions and regulatory roles in RNA biogenesis.
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Affiliation(s)
- Zhuoyi Song
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA
| | - Bongmin Bae
- Department of Molecular & Cellular Biology, Harvard University, Cambridge, MA, USA
| | - Simon Schnabl
- Department of Molecular & Cellular Biology, Harvard University, Cambridge, MA, USA
| | - Fei Yuan
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA
| | - Thareendra De Zoysa
- Department of Molecular & Cellular Biology, Harvard University, Cambridge, MA, USA
| | - Maureen V Akinyi
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA
| | - Charlotte A Le Roux
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA
| | - Karine Choquet
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Amanda J Whipple
- Department of Molecular & Cellular Biology, Harvard University, Cambridge, MA, USA.
| | - Eric L Van Nostrand
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
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8
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Liu B, Wu T, Miao BA, Ji F, Liu S, Wang P, Zhao Y, Zhong Y, Sundaram A, Zeng TB, Majcherska-Agrawal M, Keenan RJ, Pan T, He C. snoRNA-facilitated protein secretion revealed by transcriptome-wide snoRNA target identification. Cell 2025; 188:465-483.e22. [PMID: 39579764 PMCID: PMC11761385 DOI: 10.1016/j.cell.2024.10.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 09/13/2024] [Accepted: 10/24/2024] [Indexed: 11/25/2024]
Abstract
Small nucleolar RNAs (snoRNAs) are non-coding RNAs known for guiding RNA modifications, including 2'-O-methylation (Nm) and pseudouridine (Ψ). While snoRNAs may also interact with other RNAs, such as mRNA, the full repertoire of RNAs targeted by snoRNA remains elusive due to the lack of effective technologies that identify snoRNA targets transcriptome wide. Here, we develop a chemical crosslinking-based approach that comprehensively detects cellular RNA targets of snoRNAs, yielding thousands of previously unrecognized snoRNA-mRNA interactions in human cells and mouse brain tissues. Many interactions occur outside of snoRNA-guided RNA modification sites, hinting at non-canonical functions beyond RNA modification. We find that one of these snoRNAs, SNORA73, targets mRNAs that encode secretory proteins and membrane proteins. SNORA73 also interacts with 7SL RNA, part of the signal recognition particle (SRP) required for protein secretion. The mRNA-SNORA73-7SL RNA interactions enhance the association of the SNORA73-target mRNAs with SRP, thereby facilitating the secretion of encoded proteins.
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Affiliation(s)
- Bei Liu
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Tong Wu
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Bernadette A Miao
- Howard Hughes Medical Institute, Chicago, IL 60637, USA; Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA
| | - Fei Ji
- Howard Hughes Medical Institute, Chicago, IL 60637, USA; Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA; Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA
| | - Shun Liu
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Pingluan Wang
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Yutao Zhao
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Yuhao Zhong
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Arunkumar Sundaram
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA
| | - Tie-Bo Zeng
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA
| | - Marta Majcherska-Agrawal
- Howard Hughes Medical Institute, Chicago, IL 60637, USA; Committee on Genetics, Genomics & System Biology, The University of Chicago, Chicago, IL 60637, USA
| | - Robert J Keenan
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA
| | - Tao Pan
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
| | - Chuan He
- Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA; Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
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9
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Liao Y, Li R, Zhang H, Li Q, Xu X, Meng F, Sun Y. CircSugp1 interacts with CPSF6 to modulate intestinal mucosa repair by regulating alternative polyadenylation-mediated shortening of the Wdr89 3'UTR. Int Immunopharmacol 2025; 145:113793. [PMID: 39662264 DOI: 10.1016/j.intimp.2024.113793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 11/22/2024] [Accepted: 12/03/2024] [Indexed: 12/13/2024]
Abstract
Circular RNAs are a single-stranded non-coding RNAs and play an important role in the development of many diseases. Alternative polyadenylation (APA) regulates the gene 3'UTR length for controlling gene expressions. Although the APA mechanism has been widely studied in the development of diseases, there is no data on its role in the burned intestinal mucosa. We thus herein assessed the role of the circSugp1-initiating APA mechanism in the burned intestinal mucosa. CircSugp1 was downregulated in the intestinal mucosa of burned mice. CircSugp1 promoted proliferation and migration in vitro and in vivo. CircSugp1 promotes the expression of CPSF6; the overexpression of CPSF6 can shorten the gene 3'UTR within the transcript APA range. The promoting effect of circSugp1 on value-added migration was mediated by the APA regulation of the Wdr89 short 3'UTR isoform. CircSugp1 targeted the upregulation of the expression of CPSF6, followed by upregulation of the expression of Wdr89 through APA, promoting the repair of intestinal mucosal damage in burned mice.
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Affiliation(s)
- Yu Liao
- Department of Burn Surgery, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China; Department of Burn Surgery, The 71st Group Army Hospital of PLA, Xuzhou 221004, Jiangsu Province, China
| | - Ran Li
- Department of Burn Surgery, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China; Department of Burn Surgery, The 71st Group Army Hospital of PLA, Xuzhou 221004, Jiangsu Province, China
| | - Hao Zhang
- Department of Burn Surgery, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China; Department of Burn Surgery, The 71st Group Army Hospital of PLA, Xuzhou 221004, Jiangsu Province, China
| | - Qi Li
- Department of Burn Surgery, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China; Department of Burn Surgery, The 71st Group Army Hospital of PLA, Xuzhou 221004, Jiangsu Province, China
| | - Xiaoqing Xu
- Department of Burn Surgery, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China; Department of Burn Surgery, The 71st Group Army Hospital of PLA, Xuzhou 221004, Jiangsu Province, China
| | - Fanze Meng
- Department of Burn Surgery, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China; Department of Burn Surgery, The 71st Group Army Hospital of PLA, Xuzhou 221004, Jiangsu Province, China
| | - Yong Sun
- Department of Burn Surgery, The Affiliated Huaihai Hospital of Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China; Department of Burn Surgery, The 71st Group Army Hospital of PLA, Xuzhou 221004, Jiangsu Province, China.
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10
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Liu X, Liu X, Dong W, Wang P, Liu L, Liu L, E T, Wang D, Lin Y, Lin H, Ruan X, Xue Y. KHDRBS1 regulates the pentose phosphate pathway and malignancy of GBM through SNORD51-mediated polyadenylation of ZBED6 pre-mRNA. Cell Death Dis 2024; 15:802. [PMID: 39516455 PMCID: PMC11549417 DOI: 10.1038/s41419-024-07163-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/11/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
Glioblastoma is one of the most common and aggressive primary brain tumors. The aberration of metabolism is the important character of GBM cells and is tightly related to the malignancy of GBM. We mainly verified the regulatory effects of KHDRBS1, SNORD51 and ZBED6 on pentose phosphate pathway and malignant biological behavior in glioblastoma cells, such as proliferation, migration and invasion. KHDRBS1 and SNORD51 were upregulated in GBM tissues and cells. But ZBED6 had opposite tendency in GBM tissues and cells. KHDRBS1 may improve the stability of SNORD51 by binding to SNORD51, thus elevating the expression of SNORD51. More importantly, SNORD51 can competitively bind to WDR33 with 3'UTR of ZBED6 pre-mRNA which can inhibit the 3' end processing of ZBED6 pre-mRNA, thereby inhibiting the expression of ZBED6 mRNA. ZBED6 inhibited the transcription of G6PD by binding to the promoter region of G6PD. Therefore, the KHDRBS1/SNORD51/ZBED6 pathway performs an important part in regulating the pentose phosphate pathway to influence malignant biological behavior of GBM cells, providing new insights and potential targets for the treatment of GBM.
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Affiliation(s)
- Xiaoyu Liu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
| | - Xiaobai Liu
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Weiwei Dong
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Ping Wang
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
| | - Libo Liu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
| | - Lu Liu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
| | - Tiange E
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Di Wang
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Yang Lin
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
| | - Hongda Lin
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Xuelei Ruan
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China.
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China.
| | - Yixue Xue
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China.
- Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, 110004, China.
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11
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Vangoor VR, Giuliani G, de Wit M, Rangel CK, Venø MT, Schulte JT, Gomes-Duarte A, Senthilkumar K, Puhakka N, Kjems J, de Graan PNE, Pasterkamp RJ. Compartment-specific small non-coding RNA changes and nucleolar defects in human mesial temporal lobe epilepsy. Acta Neuropathol 2024; 148:61. [PMID: 39509000 PMCID: PMC11543739 DOI: 10.1007/s00401-024-02817-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 11/15/2024]
Abstract
Mesial temporal lobe epilepsy (mTLE) is a debilitating disease characterized by recurrent seizures originating from temporal lobe structures such as the hippocampus. The pathogenic mechanisms underlying mTLE are incompletely understood but include changes in the expression of non-coding RNAs in affected brain regions. Previous work indicates that some of these changes may be selective to specific sub-cellular compartments, but the full extent of these changes and how these sub-cellular compartments themselves are affected remains largely unknown. Here, we performed small RNA sequencing (RNA-seq) of sub-cellular fractions of hippocampal tissue from mTLE patients and controls to determine nuclear and cytoplasmic expression levels of microRNAs (miRNAs). This showed differential expression of miRNAs and isomiRs, several of which displayed enriched nuclear expression in mTLE. Subsequent analysis of miR-92b, the most strongly deregulated miRNA in the nucleus, showed accumulation of this miRNA in the nucleolus in mTLE and association with snoRNAs. This prompted us to further study the nucleolus in human mTLE which uncovered several defects, such as altered nucleolar size or shape, mis-localization of nucleolar proteins, and deregulation of snoRNAs, indicative of nucleolar stress. In a rat model of epilepsy, nucleolar phenotypes were detected in the latency period before the onset of spontaneous seizures, suggesting that nucleolar changes may contribute to the development of seizures and mTLE. Overall, these data for the first time implicate nucleolar defects in the pathogenesis of mTLE and provide a valuable framework for further defining the functional consequences of altered sub-cellular RNA profiles in this disease.
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Affiliation(s)
- Vamshidhar R Vangoor
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Giuliano Giuliani
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Marina de Wit
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Carolina K Rangel
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands
| | - Morten T Venø
- Interdisciplinary Nanoscience Centre, Department of Molecular Biology and Genetics, Aarhus University, 8000, Aarhus, Denmark
- Omiics ApS, 8200, Aarhus N, Denmark
| | - Joran T Schulte
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Andreia Gomes-Duarte
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
- VectorY Therapeutics, Matrix Innovation Center VI, Science Park 408, 1098 XH, Amsterdam, The Netherlands
| | - Ketharini Senthilkumar
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - Noora Puhakka
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211, Kuopio, Finland
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Centre, Department of Molecular Biology and Genetics, Aarhus University, 8000, Aarhus, Denmark
| | - Pierre N E de Graan
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CG, Utrecht, The Netherlands.
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12
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Hu X, Cui W, Liu M, Zhang F, Zhao Y, Zhang M, Yin Y, Li Y, Che Y, Zhu X, Fan Y, Deng X, Wei M, Wu H. SnoRNAs: The promising targets for anti-tumor therapy. J Pharm Anal 2024; 14:101064. [PMID: 39634568 PMCID: PMC11613181 DOI: 10.1016/j.jpha.2024.101064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 07/27/2024] [Accepted: 08/01/2024] [Indexed: 12/07/2024] Open
Abstract
Recently, small nucleolar RNAs (snoRNAs) have transcended the genomic "noise" to emerge as pivotal molecular markers due to their essential roles in tumor progression. Substantial evidence indicates a strong association between snoRNAs and critical clinical features such as tumor pathology and drug resistance. Historically, snoRNA research has concentrated on two classical mechanisms: 2'-O-ribose methylation and pseudouridylation. This review specifically summarizes the novel regulatory mechanisms and functional patterns of snoRNAs in tumors, encompassing transcriptional, post-transcriptional, and post-translational regulation. We further discuss the synergistic effect between snoRNA host genes (SNHGs) and snoRNAs in tumor progression. More importantly, snoRNAs extensively contribute to the development of tumor cell resistance as oncogenes or tumor suppressor genes. Accordingly, we provide a comprehensive review of the clinical diagnosis and treatment associated with snoRNAs and explore their significant potential as novel drug targets.
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Affiliation(s)
- Xiaoyun Hu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
- Scientific Experimental Center, School of Pharmacy, China Medical University, Shenyang, 110122, China
| | - Wanlin Cui
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Min Liu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Fangxiao Zhang
- The Second Department of Infectious Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Yingqi Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Mingrong Zhang
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Yuhang Yin
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Yalun Li
- Department of Anorectal Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China
| | - Ying Che
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Xianglong Zhu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Yuxuan Fan
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
| | - Xiaolan Deng
- Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, 91016, USA
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
- Scientific Experimental Center, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Shenyang Kangwei Medical Laboratory Analysis Co., Ltd., Shenyang, 110000, China
| | - Huizhe Wu
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Liaoning Cancer Immune Peptide Drug Engineering Technology Research Center, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, 110122, China
- Scientific Experimental Center, School of Pharmacy, China Medical University, Shenyang, 110122, China
- Shenyang Kangwei Medical Laboratory Analysis Co., Ltd., Shenyang, 110000, China
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13
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Song Z, Bae B, Schnabl S, Yuan F, De Zoysa T, Akinyi M, Le Roux C, Choquet K, Whipple A, Van Nostrand E. Mapping snoRNA-target RNA interactions in an RNA binding protein-dependent manner with chimeric eCLIP. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.19.613955. [PMID: 39345503 PMCID: PMC11429978 DOI: 10.1101/2024.09.19.613955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Small nucleolar RNAs (snoRNAs) are non-coding RNAs that function in ribosome and spliceosome biogenesis, primarily by guiding modifying enzymes to specific sites on ribosomal RNA (rRNA) and spliceosomal RNA (snRNA). However, many orphan snoRNAs remain uncharacterized, with unidentified or unvalidated targets, and studies on additional snoRNA-associated proteins are limited. We adapted an enhanced chimeric eCLIP approach to comprehensively profile snoRNA-target RNA interactions using both core and accessory snoRNA binding proteins as baits. Using core snoRNA binding proteins, we confirmed most annotated snoRNA-rRNA and snoRNA-snRNA interactions in mouse and human cell lines and called novel, high-confidence interactions for orphan snoRNAs. While some of these interactions result in chemical modification, others may have modification-independent functions. We then showed that snoRNA ribonucleoprotein complexes containing certain accessory proteins, like WDR43 and NOLC1, enriched for specific subsets of snoRNA-target RNA interactions with distinct roles in ribosome and spliceosome biogenesis. Notably, we discovered that SNORD89 guides 2'-O-methylation at two neighboring sites in U2 snRNA that are important for activating splicing, but also appear to ensure imperfect splicing for a subset of near-constitutive exons. Thus, chimeric eCLIP of snoRNA-associating proteins enables a comprehensive framework for studying snoRNA-target interactions in an RNA binding protein-dependent manner, revealing novel interactions and regulatory roles in RNA biogenesis.
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Affiliation(s)
- Zhuoyi Song
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX USA
| | - Bongmin Bae
- Department of Molecular & Cellular Biology, Harvard University, Cambridge MA USA
| | - Simon Schnabl
- Department of Molecular & Cellular Biology, Harvard University, Cambridge MA USA
| | - Fei Yuan
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX USA
| | - Thareendra De Zoysa
- Department of Molecular & Cellular Biology, Harvard University, Cambridge MA USA
| | - Maureen Akinyi
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX USA
| | - Charlotte Le Roux
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX USA
| | - Karine Choquet
- Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Québec CA
| | - Amanda Whipple
- Department of Molecular & Cellular Biology, Harvard University, Cambridge MA USA
| | - Eric Van Nostrand
- Therapeutic Innovation Center & the Verna Marrs McLean Department of Biochemistry & Molecular Pharmacology, Baylor College of Medicine, Houston, TX USA
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14
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Liu X, Xie H, Liu W, Zuo J, Li S, Tian Y, Zhao J, Bai M, Li J, Bao L, Han J, Zhang ZC. Dynamic regulation of alternative polyadenylation by PQBP1 during neurogenesis. Cell Rep 2024; 43:114525. [PMID: 39037895 DOI: 10.1016/j.celrep.2024.114525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/07/2024] [Accepted: 07/08/2024] [Indexed: 07/24/2024] Open
Abstract
Alternative polyadenylation (APA) is a critical post-transcriptional process that generates mRNA isoforms with distinct 3' untranslated regions (3' UTRs), thereby regulating mRNA localization, stability, and translational efficiency. Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Despite its recognized significance, the precise regulatory mechanisms governing cell-type-specific APA remain unclear. In this study, we uncover PQBP1 as an emerging APA regulator that actively maintains cell-specific APA profiles in neural progenitor cells (NPCs) and delicately manages the equilibrium between NPC proliferation and differentiation. Multi-omics analysis shows that PQBP1 directly interacts with the upstream UGUA elements, impeding the recruitment of the CFIm complex and influencing polyadenylation site selection within genes associated with the cell cycle. Our findings elucidate the molecular mechanism by which PQBP1 orchestrates dynamic APA changes during neurogenesis, providing valuable insights into the precise regulation of cell-type-specific APA and the underlying pathogenic mechanisms in neurodevelopmental disorders.
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Affiliation(s)
- Xian Liu
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China
| | - Hao Xie
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China
| | - Wenhua Liu
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China
| | - Jian Zuo
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China
| | - Song Li
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China
| | - Yao Tian
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China
| | | | - Meizhu Bai
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jinsong Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lan Bao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Junhai Han
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China.
| | - Zi Chao Zhang
- School of Life Science and Technology, The Key Laboratory of Developmental Genes and Human Disease, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Southeast University, Nanjing 210096, China.
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15
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Liu L, Manley JL. Modulation of diverse biological processes by CPSF, the master regulator of mRNA 3' ends. RNA (NEW YORK, N.Y.) 2024; 30:1122-1140. [PMID: 38986572 PMCID: PMC11331416 DOI: 10.1261/rna.080108.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 06/27/2024] [Indexed: 07/12/2024]
Abstract
The cleavage and polyadenylation specificity factor (CPSF) complex plays a central role in the formation of mRNA 3' ends, being responsible for the recognition of the poly(A) signal sequence, the endonucleolytic cleavage step, and recruitment of poly(A) polymerase. CPSF has been extensively studied for over three decades, and its functions and those of its individual subunits are becoming increasingly well-defined, with much current research focusing on the impact of these proteins on the normal functioning or disease/stress states of cells. In this review, we provide an overview of the general functions of CPSF and its subunits, followed by a discussion of how they exert their functions in a surprisingly diverse variety of biological processes and cellular conditions. These include transcription termination, small RNA processing, and R-loop prevention/resolution, as well as more generally cancer, differentiation/development, and infection/immunity.
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Affiliation(s)
- Lizhi Liu
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
| | - James L Manley
- Department of Biological Sciences, Columbia University, New York, New York 10027, USA
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16
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Shen LP, Zhang WC, Deng JR, Qi ZH, Lin ZW, Wang ZD. Advances in the mechanism of small nucleolar RNA and its role in DNA damage response. Mil Med Res 2024; 11:53. [PMID: 39118131 PMCID: PMC11308251 DOI: 10.1186/s40779-024-00553-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 07/08/2024] [Indexed: 08/10/2024] Open
Abstract
Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.
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Affiliation(s)
- Li-Ping Shen
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Wen-Cheng Zhang
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Jia-Rong Deng
- Graduate Collaborative Training Base of Academy of Military Sciences, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Zhen-Hua Qi
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Zhong-Wu Lin
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Zhi-Dong Wang
- Department of Radiobiology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
- Graduate Collaborative Training Base of Academy of Military Sciences, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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17
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Chauhan W, Sudharshan SJ, Kafle S, Zennadi R. SnoRNAs: Exploring Their Implication in Human Diseases. Int J Mol Sci 2024; 25:7202. [PMID: 39000310 PMCID: PMC11240930 DOI: 10.3390/ijms25137202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Small nucleolar RNAs (snoRNAs) are earning increasing attention from research communities due to their critical role in the post-transcriptional modification of various RNAs. These snoRNAs, along with their associated proteins, are crucial in regulating the expression of a vast array of genes in different human diseases. Primarily, snoRNAs facilitate modifications such as 2'-O-methylation, N-4-acetylation, and pseudouridylation, which impact not only ribosomal RNA (rRNA) and their synthesis but also different RNAs. Functionally, snoRNAs bind with core proteins to form small nucleolar ribonucleoproteins (snoRNPs). These snoRNAs then direct the protein complex to specific sites on target RNA molecules where modifications are necessary for either standard cellular operations or the regulation of pathological mechanisms. At these targeted sites, the proteins coupled with snoRNPs perform the modification processes that are vital for controlling cellular functions. The unique characteristics of snoRNAs and their involvement in various non-metabolic and metabolic diseases highlight their potential as therapeutic targets. Moreover, the precise targeting capability of snoRNAs might be harnessed as a molecular tool to therapeutically address various disease conditions. This review delves into the role of snoRNAs in health and disease and explores the broad potential of these snoRNAs as therapeutic agents in human pathologies.
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Affiliation(s)
| | | | | | - Rahima Zennadi
- Department of Physiology, University of Tennessee Health Science Center, 71 S. Manassas St., Memphis, TN 38103, USA; (W.C.); (S.S.); (S.K.)
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18
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Chabronova A, Holmes TL, Hoang DM, Denning C, James V, Smith JGW, Peffers MJ. SnoRNAs in cardiovascular development, function, and disease. Trends Mol Med 2024; 30:562-578. [PMID: 38523014 DOI: 10.1016/j.molmed.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/26/2024]
Abstract
Small nucleolar RNAs (snoRNAs) are emerging as important regulators of cardiovascular (patho)biology. Several roles of snoRNAs have recently been identified in heart development and congenital heart diseases, as well as their dynamic regulation in hypertrophic and dilated cardiomyopathies, coronary heart disease (CHD), myocardial infarction (MI), cardiac fibrosis, and heart failure. Furthermore, reports of changes in vesicular snoRNA expression and altered levels of circulating snoRNAs in response to cardiac stress suggest that snoRNAs also function in cardiac signaling and intercellular communication. In this review, we summarize and discuss key findings and outline the clinical potential of snoRNAs considering current challenges and gaps in the field of cardiovascular diseases (CVDs).
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Affiliation(s)
- Alzbeta Chabronova
- Department of Musculoskeletal Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, UK.
| | - Terri L Holmes
- Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7UQ, UK
| | - Duc M Hoang
- Department of Stem Cell Biology, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
| | - Chris Denning
- Department of Stem Cell Biology, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
| | - Victoria James
- School of Veterinary Medicine and Science, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
| | - James G W Smith
- Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7UQ, UK
| | - Mandy J Peffers
- Department of Musculoskeletal Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, UK
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19
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Zeng Y, Yuan Z, Li J, Yang L, Li C, Xiang Y, Wu L, Xia T, Zhong L, Li Y, Wu N. Small non-coding RNA signatures in atrial appendages of patients with atrial fibrillation. J Cell Mol Med 2024; 28:e18483. [PMID: 39051629 PMCID: PMC11193094 DOI: 10.1111/jcmm.18483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/16/2024] [Accepted: 05/28/2024] [Indexed: 07/27/2024] Open
Abstract
The development of high-throughput technologies has enhanced our understanding of small non-coding RNAs (sncRNAs) and their crucial roles in various diseases, including atrial fibrillation (AF). This study aimed to systematically delineate sncRNA profiles in AF patients. PANDORA-sequencing was used to examine the sncRNA profiles of atrial appendage tissues from AF and non-AF patients. Differentially expressed sncRNAs were identified using the R package DEGseq 2 with a fold change >2 and p < 0.05. The target genes of the differentially expressed sncRNAs were predicted using MiRanda and RNAhybrid. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. In AF patients, the most abundant sncRNAs were ribosomal RNA-derived small RNAs (rsRNAs), followed by transfer RNA-derived small RNAs (tsRNAs), and microRNAs (miRNAs). Compared with non-AF patients, 656 rsRNAs, 45 miRNAs, 191 tsRNAs and 51 small nucleolar RNAs (snoRNAs) were differentially expressed in AF patients, whereas no significantly differentially expressed piwi-interacting RNAs were identified. Two out of three tsRNAs were confirmed to be upregulated in AF patients by quantitative reverse transcriptase polymerase chain reaction, and higher plasma levels of tsRNA 5006c-LysCTT were associated with a 2.55-fold increased risk of all-cause death in AF patients (hazard ratio: 2.55; 95% confidence interval, 1.56-4.17; p < 0.001). Combined with our previous transcriptome sequencing results, 32 miRNA, 31 snoRNA, 110 nucleus-encoded tsRNA, and 33 mitochondria-encoded tsRNA target genes were dysregulated in AF patients. GO and KEGG analyses revealed enrichment of differentially expressed sncRNA target genes in AF-related pathways, including the 'calcium signaling pathway' and 'adrenergic signaling in cardiomyocytes.' The dysregulated sncRNA profiles in AF patients suggest their potential regulatory roles in AF pathogenesis. Further research is needed to investigate the specific mechanisms of sncRNAs in the development of AF and to explore potential biomarkers for AF treatment and prognosis.
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Affiliation(s)
- Yuhong Zeng
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Zhiquan Yuan
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Jun Li
- Thoracic and Cardiac Surgery, Southwest HospitalThe First Affiliated Hospital of Army Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Lanqing Yang
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Chengying Li
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Ying Xiang
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Long Wu
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Tingting Xia
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Li Zhong
- Cardiovascular Disease CenterThird Affiliated Hospital of Chongqing Medical UniversityChongqingPeople's Republic of China
| | - Yafei Li
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
| | - Na Wu
- Department of Epidemiology, College of Preventive MedicineArmy Medical University (Third Military Medical University)ChongqingPeople's Republic of China
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20
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Zacchini F, Barozzi C, Venturi G, Montanaro L. How snoRNAs can contribute to cancer at multiple levels. NAR Cancer 2024; 6:zcae005. [PMID: 38406265 PMCID: PMC10894041 DOI: 10.1093/narcan/zcae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/05/2024] [Accepted: 02/12/2024] [Indexed: 02/27/2024] Open
Abstract
snoRNAs are a class of non-coding RNAs known to guide site specifically RNA modifications such as 2'-O-methylation and pseudouridylation. Recent results regarding snoRNA alterations in cancer has been made available and suggest their potential evaluation as diagnostic and prognostic biomarkers. A large part of these data, however, was not consistently confirmed and failed to provide mechanistic insights on the contribution of altered snoRNA expression to the neoplastic process. Here, we aim to critically review the available literature on snoRNA in cancer focusing on the studies elucidating the functional consequences of their deregulation. Beyond the canonical guide function in RNA processing and modification we also considered additional roles in which snoRNA, in various forms and through different modalities, are involved and that have been recently reported.
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Affiliation(s)
- Federico Zacchini
- Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, I-40138 Bologna, Italy
| | - Chiara Barozzi
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna I-40138, Italy
| | - Giulia Venturi
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna I-40138, Italy
- Centre for Applied Biomedical Research – CRBA, University of Bologna, Sant’Orsola Hospital, Bologna I-40138, Italy
| | - Lorenzo Montanaro
- Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, I-40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna I-40138, Italy
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21
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Lan YZ, Wu Z, Chen WJ, Fang ZX, Yu XN, Wu HT, Liu J. Small nucleolar RNA and its potential role in the oncogenesis and development of colorectal cancer. World J Gastroenterol 2024; 30:115-127. [PMID: 38312115 PMCID: PMC10835520 DOI: 10.3748/wjg.v30.i2.115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Small nucleolar RNAs (snoRNAs) represent a class of non-coding RNAs that play pivotal roles in post-transcriptional RNA processing and modification, thereby contributing significantly to the maintenance of cellular functions related to protein synthesis. SnoRNAs have been discovered to possess the ability to influence cell fate and alter disease progression, holding immense potential in controlling human diseases. It is suggested that the dysregulation of snoRNAs in cancer exhibits differential expression across various cancer types, stages, metastasis, treatment response and/or prognosis in patients. On the other hand, colorectal cancer (CRC), a prevalent malignancy of the digestive system, is characterized by high incidence and mortality rates, ranking as the third most common cancer type. Recent research indicates that snoRNA dysregulation is associated with CRC, as snoRNA expression significantly differs between normal and cancerous conditions. Consequently, assessing snoRNA expression level and function holds promise for the prognosis and diagnosis of CRC. Nevertheless, current comprehension of the potential roles of snoRNAs in CRC remains limited. This review offers a comprehensive survey of the aberrant regulation of snoRNAs in CRC, providing valuable insights into the discovery of novel biomarkers, therapeutic targets, and potential tools for the diagnosis and treatment of CRC and furnishing critical cues for advancing research into CRC and the judicious selection of therapeutic targets.
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Affiliation(s)
- Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xin-Ning Yu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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22
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Kharaz YA, Zamboulis DE, Fang Y, Welting TJM, Peffers MJ, Comerford EJ. Small RNA signatures of the anterior cruciate ligament from patients with knee joint osteoarthritis. Front Mol Biosci 2023; 10:1266088. [PMID: 38187089 PMCID: PMC10768046 DOI: 10.3389/fmolb.2023.1266088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
Introduction: The anterior cruciate ligament (ACL) is susceptible to degeneration, resulting in joint pain, reduced mobility, and osteoarthritis development. There is currently a paucity of knowledge on how anterior cruciate ligament degeneration and disease leads to osteoarthritis. Small non-coding RNAs (sncRNAs), such as microRNAs and small nucleolar RNA (snoRNA), have diverse roles, including regulation of gene expression. Methods: We profiled the sncRNAs of diseased osteoarthritic ACLs to provide novel insights into osteoarthritis development. Small RNA sequencing from the ACLs of non- or end-stage human osteoarthritic knee joints was performed. Significantly differentially expressed sncRNAs were defined, and bioinformatics analysis was undertaken. Results and Discussion: A total of 184 sncRNAs were differentially expressed: 68 small nucleolar RNAs, 26 small nuclear RNAs (snRNAs), and 90 microRNAs. We identified both novel and recognized (miR-206, -365, and -29b and -29c) osteoarthritis-related microRNAs and other sncRNAs (including SNORD72, SNORD113, and SNORD114). Significant pathway enrichment of differentially expressed miRNAs includes differentiation of the muscle, inflammation, proliferation of chondrocytes, and fibrosis. Putative mRNAs of the microRNA target genes were associated with the canonical pathways "hepatic fibrosis signaling" and "osteoarthritis." The establishing sncRNA signatures of ACL disease during osteoarthritis could serve as novel biomarkers and potential therapeutic targets in ACL degeneration and osteoarthritis development.
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Affiliation(s)
- Yalda A. Kharaz
- Department of Musculoskeletal Ageing Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Danae E. Zamboulis
- Comparative Biomedical Sciences, Royal Veterinary College, London, United Kingdom
| | - Yongxiang Fang
- Centre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Tim J. M. Welting
- Department of Orthopaedic Surgery, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Mandy J. Peffers
- Department of Musculoskeletal Ageing Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Eithne J. Comerford
- Department of Musculoskeletal Ageing Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
- Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
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23
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Matveeva A, Vinogradov D, Zhuravlev E, Semenov D, Vlassov V, Stepanov G. Intron Editing Reveals SNORD-Dependent Maturation of the Small Nucleolar RNA Host Gene GAS5 in Human Cells. Int J Mol Sci 2023; 24:17621. [PMID: 38139448 PMCID: PMC10743478 DOI: 10.3390/ijms242417621] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/13/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
The GAS5 gene encodes a long non-coding RNA (lncRNA) and intron-located small nucleolar RNAs (snoRNAs). Its structure, splice variants, and diverse functions in mammalian cells have been thoroughly investigated. However, there are still no data on a successful knockout of GAS5 in human cells, with most of the loss-of-function experiments utilizing standard techniques to produce knockdowns. By using CRISPR/Cas9 to introduce double-strand breaks in the terminal intronic box C/D snoRNA genes (SNORDs), we created monoclonal cell lines carrying continuous deletions in one of the GAS5 alleles. The levels of GAS5-encoded box C/D snoRNAs and lncRNA GAS5 were assessed, and the formation of the novel splice variants was analyzed. To comprehensively evaluate the influence of specific SNORD mutations, human cell lines with individual mutations in SNORD74 and SNORD81 were obtained. Specific mutations in SNORD74 led to the downregulation of all GAS5-encoded SNORDs and GAS5 lncRNA. Further analysis revealed that SNORD74 contains a specific regulatory element modulating the maturation of the GAS5 precursor transcript. The results demonstrate that the maturation of GAS5 occurs through the m6A-associated pathway in a SNORD-dependent manner, which is a quite intriguing epitranscriptomic mechanism.
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Affiliation(s)
| | | | | | | | | | - Grigory Stepanov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russia; (A.M.); (D.V.); (E.Z.); (D.S.)
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24
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Sun X, Wang G, Luo W, Gu H, Ma W, Wei X, Liu D, Jia S, Cao S, Wang Y, Yuan Z. Small but strong: the emerging role of small nucleolar RNA in cardiovascular diseases. Front Cell Dev Biol 2023; 11:1292925. [PMID: 38033868 PMCID: PMC10682241 DOI: 10.3389/fcell.2023.1292925] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality and disability worldwide. Numerous studies have demonstrated that non-coding RNAs (ncRNAs) play a primary role in CVD development. Therefore, studies on the mechanisms of ncRNAs are essential for further efforts to prevent and treat CVDs. Small nucleolar RNAs (snoRNAs) are a novel species of non-conventional ncRNAs that guide post-transcriptional modifications and the subsequent maturation of small nuclear RNA and ribosomal RNA. Evidently, snoRNAs are extensively expressed in human tissues and may regulate different illnesses. Particularly, as the next-generation sequencing techniques have progressed, snoRNAs have been shown to be differentially expressed in CVDs, suggesting that they may play a role in the occurrence and progression of cardiac illnesses. However, the molecular processes and signaling pathways underlying the function of snoRNAs remain unidentified. Therefore, it is of great value to comprehensively investigate the association between snoRNAs and CVDs. The aim of this review was to collate existing literature on the biogenesis, characteristics, and potential regulatory mechanisms of snoRNAs. In particular, we present a scientific update on these snoRNAs and their relevance to CVDs in an effort to cast new light on the functions of snoRNAs in the clinical diagnosis of CVDs.
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Affiliation(s)
- Xue Sun
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Gebang Wang
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, Shenyang, Liaoning, China
| | - Wenting Luo
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Hui Gu
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wei Ma
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaowei Wei
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Dan Liu
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Shanshan Jia
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Songying Cao
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Wang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhengwei Yuan
- Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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25
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Yin Y, Shen X. Noncoding RNA-chromatin association: Functions and mechanisms. FUNDAMENTAL RESEARCH 2023; 3:665-675. [PMID: 38933302 PMCID: PMC11197541 DOI: 10.1016/j.fmre.2023.03.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/12/2023] [Accepted: 03/23/2023] [Indexed: 06/28/2024] Open
Abstract
Pervasive transcription of the mammalian genome produces hundreds of thousands of noncoding RNAs (ncRNAs). Numerous studies have suggested that some of these ncRNAs regulate multiple cellular processes and play important roles in physiological and pathological processes. Notably, a large subset of ncRNAs is enriched on chromatin and participates in regulating gene expression and the dynamics of chromatin structure and status. In this review, we summarize recent advances in the functional study of chromatin-associated ncRNAs and mechanistic insights into how these ncRNAs associate with chromatin. We also discuss the potential future challenges which still need to be overcome in this field.
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Affiliation(s)
- Yafei Yin
- Department of Cell Biology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Yuhangtang Road, Hangzhou, Zhejiang 310058, China
| | - Xiaohua Shen
- Tsinghua-Peking Center for Life Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
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26
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Deeksha W, Abhishek S, Giri J, Rajakumara E. Regulation of PARP1 and its apoptotic variant activity by single-stranded DNA. FEBS J 2023; 290:4533-4542. [PMID: 37246313 DOI: 10.1111/febs.16875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/06/2023] [Accepted: 05/25/2023] [Indexed: 05/30/2023]
Abstract
PARP1 is a nuclear protein involved in the maintenance of genomic stability. It catalyses the formation of poly(ADP-ribose) (PAR) to recruit repair proteins at the site of DNA lesions, such as double-strand and single-strand breaks. In the process of DNA replication or repair, there could occur stretch of ssDNA, usually protected by ssDNA binding proteins, but when present in abundance can turn into DNA beaks and cause cell death. PARP1 is an extremely sensitive sensor of DNA breaks; however, the interaction of PARP1 with single-stranded DNA (ssDNA) remains unexplored. Here, we report that the two Zn-fingers, ZnF1 and ZnF2, of PARP1, mediate high-affinity recognition of ssDNA. Our studies suggest that although PAR and ssDNA are chemical analogues, they are recognized by a distinct set of domains of PARP1, yet PAR not only induces dislodging of ssDNA from PARP1 but also hampers the ssDNA-dependent PARP1 activity. It is noteworthy that PAR carrier apoptotic fragment PARP1ΔZnF1-2 gets cleaved from PARP1 to facilitate apoptosis, leaving behind the DNA-bound ZnF1-ZnF2PARP1 . Our studies demonstrate that the PARP1ΔZnF1-2 is competent for ssDNA-dependent stimulation only in the presence of another apoptotic fragment ZnF1-ZnF2PARP1 , suggesting the indispensability of DNA-bound ZnF1-ZnF2PARP1 dual domains for the same.
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Affiliation(s)
- Waghela Deeksha
- Macromolecular Structural Biology Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, India
| | - Suman Abhishek
- Macromolecular Structural Biology Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, India
| | - Jyotsnendu Giri
- Department of Biomedical Engineering, Indian Institute of Technology, Hyderabad, India
| | - Eerappa Rajakumara
- Macromolecular Structural Biology Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, India
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27
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Challakkara MF, Chhabra R. snoRNAs in hematopoiesis and blood malignancies: A comprehensive review. J Cell Physiol 2023; 238:1207-1225. [PMID: 37183323 DOI: 10.1002/jcp.31032] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/29/2023] [Accepted: 04/04/2023] [Indexed: 05/16/2023]
Abstract
Small nucleolar RNAs (snoRNAs) are noncoding RNA molecules of highly variable size, usually ranging from 60 to 150 nucleotides. They are classified into H/ACA box snoRNAs, C/D box snoRNAs, and scaRNAs. Their functional profile includes biogenesis of ribosomes, processing of rRNAs, 2'-O-methylation and pseudouridylation of RNAs, alternative splicing and processing of mRNAs and the generation of small RNA molecules like miRNA. The snoRNAs have been observed to have an important role in hematopoiesis and malignant hematopoietic conditions including leukemia, lymphoma, and multiple myeloma. Blood malignancies arise in immune system cells or the bone marrow due to chromosome abnormalities. It has been estimated that annually over 1.25 million cases of blood cancer occur worldwide. The snoRNAs often show a differential expression profile in blood malignancies. Recent reports associate the abnormal expression of snoRNAs with the inhibition of apoptosis, uncontrolled cell proliferation, angiogenesis, and metastasis. This implies that targeting snoRNAs could be a potential way to treat hematologic malignancies. In this review, we describe the various functions of snoRNAs, their role in hematopoiesis, and the consequences of their dysregulation in blood malignancies. We also evaluate the potential of the dysregulated snoRNAs as biomarkers and therapeutic targets for blood malignancies.
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Affiliation(s)
- Mohamed Fahad Challakkara
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Ravindresh Chhabra
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
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28
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Zhang Q, Bi Z, Song X, Zhang Y, Wang S, Xie L, Song X. Tumor-educated platelet SNORA58, SNORA68 and SNORD93 as novel diagnostic biomarkers for esophageal cancer. Future Oncol 2023; 19:651-661. [PMID: 37129021 DOI: 10.2217/fon-2023-0129] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2023] Open
Abstract
Aim: The purpose of this study was to evaluate whether tumor-educated platelet (TEP) snoRNAs could be used as a diagnostic biomarker for esophageal cancer (ESCA). Methods: Platelet precipitates were obtained from platelet-rich plasma by low-speed centrifugation, and total RNA was extracted from platelets using Trizol™ reagent. RT-qPCR was used to detect snoRNA expression, and the receiver operating characteristic was used to assess its diagnostic potential. Results: SNORA58, SNORA68 and SNORD93 were significantly upregulated in TEPs from ESCA patients and early-stage patients compared with healthy controls. Importantly, the three snoRNAs were capable of serving as circulating biomarkers of diagnostics and early diagnosis of ESCA, possessing areas under the curve of 0.846 and 0.857, respectively. Conclusion: TEP SNORA58, SNORA68 and SNORD93 could potentially serve as noninvasive biomarkers for diagnosis and early diagnosis of ESCA.
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Affiliation(s)
- Qianru Zhang
- Department of Clinical Laboratory, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Zhao Bi
- Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Xingguo Song
- Department of Clinical Laboratory, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Yue Zhang
- Department of Clinical Laboratory, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Shiwen Wang
- Department of Clinical Laboratory, Shandong Cancer Hospital & Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Li Xie
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Xianrang Song
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital & Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
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29
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Analysis of Expression Pattern of snoRNAs in Human Cells A549 Infected by Influenza A Virus. Int J Mol Sci 2022; 23:ijms232213666. [PMID: 36430145 PMCID: PMC9696202 DOI: 10.3390/ijms232213666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 10/20/2022] [Accepted: 10/29/2022] [Indexed: 11/09/2022] Open
Abstract
Small nucleolar RNAs (snoRNAs) are a highly expressed class of non-coding RNAs known for their role in guiding post-transcriptional modifications of ribosomal RNAs and small nuclear RNAs. Emerging studies suggest that snoRNAs are also implicated in regulating other vital cellular processes, such as pre-mRNA splicing and 3'-processing of mRNAs, and in the development of cancer and viral infections. There is an emerging body of evidence for specific snoRNA's involvement in the optimal replication of RNA viruses. In order to investigate the expression pattern of snoRNAs during influenza A viral infection, we performed RNA sequencing analysis of the A549 human cell line infected by influenza virus A/Puerto Rico/8/1934 (H1N1). We identified 66 that were upregulated and 55 that were downregulated in response to influenza A virus infection. The increased expression of most C/D-box snoRNAs was associated with elevated levels of 5'- and 3'-short RNAs derived from this snoRNA. Analysis of the poly(A)+ RNA sequencing data indicated that most of the differentially expressed snoRNAs synthesis was not correlated with the corresponding host genes expression. Furthermore, influenza A viral infection led to an imbalance in the expression of genes responsible for C/D small nucleolar ribonucleoprotein particles' biogenesis. In summary, our results indicate that the expression pattern of snoRNAs in A549 cells is significantly altered during influenza A viral infection.
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30
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Bergeron D, Paraqindes H, Fafard-Couture É, Deschamps-Francoeur G, Faucher-Giguère L, Bouchard-Bourelle P, Abou Elela S, Catez F, Marcel V, Scott M. snoDB 2.0: an enhanced interactive database, specializing in human snoRNAs. Nucleic Acids Res 2022; 51:D291-D296. [PMID: 36165892 PMCID: PMC9825428 DOI: 10.1093/nar/gkac835] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/06/2022] [Accepted: 09/16/2022] [Indexed: 01/29/2023] Open
Abstract
snoDB is an interactive database of human small nucleolar RNAs (snoRNAs) that includes up-to-date information on snoRNA features, genomic location, conservation, host gene, snoRNA-RNA targets and snoRNA abundance and provides links to other resources. In the second edition of this database (snoDB 2.0), we added an entirely new section on ribosomal RNA (rRNA) chemical modifications guided by snoRNAs with easy navigation between the different rRNA versions used in the literature and experimentally measured levels of modification. We also included new layers of information, including snoRNA motifs, secondary structure prediction, snoRNA-protein interactions, copy annotations and low structure bias expression data in a wide panel of tissues and cell lines to bolster functional probing of snoRNA biology. Version 2.0 features updated identifiers, more links to external resources and duplicate entry resolution. As a result, snoDB 2.0, which is freely available at https://bioinfo-scottgroup.med.usherbrooke.ca/snoDB/, represents a one-stop shop for snoRNA features, rRNA modification targets, functional impact and potential regulators.
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Affiliation(s)
- Danny Bergeron
- Département de biochimie et génomique fonctionnelle, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1E 4K8, Canada
| | - Hermes Paraqindes
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France,Centre Léon Bérard, F-69008 Lyon, France,Université de Lyon 1, F-69000 Lyon, France
| | - Étienne Fafard-Couture
- Département de biochimie et génomique fonctionnelle, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1E 4K8, Canada
| | - Gabrielle Deschamps-Francoeur
- Département de biochimie et génomique fonctionnelle, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1E 4K8, Canada
| | - Laurence Faucher-Giguère
- Département de microbiologie et d’infectiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1E 4K8, Canada
| | - Philia Bouchard-Bourelle
- Département de biochimie et génomique fonctionnelle, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1E 4K8, Canada
| | - Sherif Abou Elela
- Département de microbiologie et d’infectiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec J1E 4K8, Canada
| | - Frédéric Catez
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France,Centre Léon Bérard, F-69008 Lyon, France,Université de Lyon 1, F-69000 Lyon, France,Institut Convergence PLAsCAN, F-69373 Lyon, France
| | - Virginie Marcel
- Inserm U1052, CNRS UMR5286 Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France,Centre Léon Bérard, F-69008 Lyon, France,Université de Lyon 1, F-69000 Lyon, France,Institut Convergence PLAsCAN, F-69373 Lyon, France
| | - Michelle S Scott
- To whom correspondence should be addressed. Tel: +1 819 821 8000 (Ext 72123);
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Dong J, Wang H, Zhang Z, Yang L, Qian X, Qian W, Han Y, Huang H, Qian P. Small but strong: Pivotal roles and potential applications of snoRNAs in hematopoietic malignancies. Front Oncol 2022; 12:939465. [PMID: 36033520 PMCID: PMC9413531 DOI: 10.3389/fonc.2022.939465] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Small nucleolar RNAs (snoRNAs) belong to a family of noncoding RNAs that are 60-300 nucleotides in length, and they are classified into two classes according to their structure and function: C/D box snoRNAs, playing an essential role in 2’-O-methylation modification on ribosomal RNA; H/ACA box snoRNAs, involved in the pseudouridylation of rRNA. SnoRNAs with unclear functions, no predictable targets, and unusual subcellular locations are called orphan snoRNAs. Recent studies have revealed abnormal expression and demonstrated the pivotal roles of snoRNAs and their host genes in various types of hematological malignancies. This review discusses recent discoveries concerning snoRNAs in a variety of hematological malignancies, including multiple myeloma, lymphoma and leukemia, and sheds light on the application of snoRNAs as diagnostic and prognostic markers as well as therapeutic targets of hematological malignancies in the future.
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Affiliation(s)
- Jian Dong
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Hui Wang
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Zhaoru Zhang
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Lin Yang
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Xinyue Qian
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Wenchang Qian
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - Yingli Han
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
| | - He Huang
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Pengxu Qian, ; He Huang,
| | - Pengxu Qian
- Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
- *Correspondence: Pengxu Qian, ; He Huang,
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32
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Dysregulation of Small Nucleolar RNAs in B-Cell Malignancies. Biomedicines 2022; 10:biomedicines10061229. [PMID: 35740251 PMCID: PMC9219770 DOI: 10.3390/biomedicines10061229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 01/17/2023] Open
Abstract
Small nucleolar RNAs (snoRNAs) are responsible for post-transcriptional modification of ribosomal RNAs, transfer RNAs and small nuclear RNAs, and thereby have important regulatory functions in mRNA splicing and protein translation. Several studies have shown that snoRNAs are dysregulated in human cancer and may play a role in cancer initiation and progression. In this review, we focus on the role of snoRNAs in normal and malignant B-cell development. SnoRNA activity appears to be essential for normal B-cell differentiation and dysregulated expression of sno-RNAs is determined in B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell non-Hodgkin’s lymphoma, and plasma cell neoplasms. SnoRNA expression is associated with cytogenetic/molecular subgroups and clinical outcome in patients with B-cell malignancies. Translocations involving snoRNAs have been described as well. Here, we discuss the different aspects of snoRNAs in B-cell malignancies and report on their role in oncogenic transformation, which may be useful for the development of novel diagnostic biomarkers or therapeutic targets.
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Nir R, Hoernes TP, Muramatsu H, Faserl K, Karikó K, Erlacher MD, Sas-Chen A, Schwartz S. A systematic dissection of determinants and consequences of snoRNA-guided pseudouridylation of human mRNA. Nucleic Acids Res 2022; 50:4900-4916. [PMID: 35536311 PMCID: PMC9122591 DOI: 10.1093/nar/gkac347] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 04/18/2022] [Accepted: 04/24/2022] [Indexed: 12/25/2022] Open
Abstract
RNA can be extensively modified post-transcriptionally with >170 covalent modifications, expanding its functional and structural repertoire. Pseudouridine (Ψ), the most abundant modified nucleoside in rRNA and tRNA, has recently been found within mRNA molecules. It remains unclear whether pseudouridylation of mRNA can be snoRNA-guided, bearing important implications for understanding the physiological target spectrum of snoRNAs and for their potential therapeutic exploitation in genetic diseases. Here, using a massively parallel reporter based strategy we simultaneously interrogate Ψ levels across hundreds of synthetic constructs with predesigned complementarity against endogenous snoRNAs. Our results demonstrate that snoRNA-mediated pseudouridylation can occur on mRNA targets. However, this is typically achieved at relatively low efficiencies, and is constrained by mRNA localization, snoRNA expression levels and the length of the snoRNA:mRNA complementarity stretches. We exploited these insights for the design of snoRNAs targeting pseudouridylation at premature termination codons, which was previously shown to suppress translational termination. However, in this and follow-up experiments in human cells we observe no evidence for significant levels of readthrough of pseudouridylated stop codons. Our study enhances our understanding of the scope, 'design rules', constraints and consequences of snoRNA-mediated pseudouridylation.
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Affiliation(s)
- Ronit Nir
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Thomas Philipp Hoernes
- Institute of Genomics and RNomics, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Hiromi Muramatsu
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.,Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Klaus Faserl
- Institute of Clinical Biochemistry, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Katalin Karikó
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.,BioNTech RNA Pharmaceuticals, Mainz, Germany
| | | | - Aldema Sas-Chen
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.,The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Schraga Schwartz
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel
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Ran Y, Huang S, Shi J, Feng Q, Deng Y, Xiang AP, Yao C. CFIm25 regulates human stem cell function independently of its role in mRNA alternative polyadenylation. RNA Biol 2022; 19:686-702. [PMID: 35491945 PMCID: PMC9067535 DOI: 10.1080/15476286.2022.2071025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
It has recently been shown that CFIm25, a canonical mRNA 3’ processing factor, could play a variety of physiological roles through its molecular function in the regulation of mRNA alternative polyadenylation (APA). Here, we used CRISPR/Cas9-mediated gene editing approach in human embryonic stem cells (hESCs) for CFIm25, and obtained three gene knockdown/mutant cell lines. CFIm25 gene editing resulted in higher proliferation rate and impaired differentiation potential for hESCs, with these effects likely to be directly regulated by the target genes, including the pluripotency factor rex1. Mechanistically, we unexpected found that perturbation in CFIm25 gene expression did not significantly affect cellular mRNA 3’ processing efficiency and APA profile. Rather, we provided evidences that CFIm25 may impact RNA polymerase II (RNAPII) occupancy at the body of transcribed genes, and promote the expression level of a group of transcripts associated with cellular proliferation and/or differentiation. Taken together, these results reveal novel mechanisms underlying CFIm25ʹs modulation in determination of cell fate, and provide evidence that the process of mammalian gene transcription may be regulated by an mRNA 3’ processing factor.
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Affiliation(s)
- Yi Ran
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Shanshan Huang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Junjie Shi
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Qiumin Feng
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Yanhui Deng
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Chengguo Yao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
- Department of Genetics and Cell Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
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van Ingen E, van den Homberg DAL, van der Bent ML, Mei H, Papac-Milicevic N, Kremer V, Boon RA, Quax PHA, Wojta J, Nossent AY. C/D box snoRNA SNORD113-6/AF357425 plays a dual role in integrin signalling and arterial fibroblast function via pre-mRNA processing and 2'O-ribose methylation. Hum Mol Genet 2022; 31:1051-1066. [PMID: 34673944 PMCID: PMC8976432 DOI: 10.1093/hmg/ddab304] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 09/03/2021] [Accepted: 10/13/2021] [Indexed: 11/28/2022] Open
Abstract
We have previously shown that C/D box small nucleolar RNAs (snoRNAs) transcribed from the DLK1-DIO3 locus on human chromosome 14 (14q32) are associated with cardiovascular disease. DLK1-DIO3 snoRNAs are 'orphan snoRNAs' that have no known targets. We aimed to identify RNA targets and elucidate the mechanism-of-action of human SNORD113-6 (AF357425 in mice). As AF357425-knockout cells were non-viable, we induced overexpression or inhibition of AF357425 in primary murine fibroblasts and performed RNA-Seq. We identified several pre-mRNAs with conserved AF357425/SNORD113-6 D'-seed binding sites in the last exon/3' untranslated region (3'UTR), which directed pre-mRNA processing and splice-variant-specific protein expression. We also pulled down the snoRNA-associated methyltransferase fibrillarin from AF357425-High versus AF357425-Low fibroblast lysates, followed by RNA isolation, ribosomal RNA depletion and RNA-Seq. Identifying mostly mRNAs, we subjected these to PANTHER pathway analysis and observed enrichment for genes in the integrin pathway. We confirmed 2'O-ribose methylation in six integrin pathway mRNAs (MAP2K1, ITGB3, ITGA7, PARVB, NTN4 and FLNB). Methylation and mRNA expressions were decreased while mRNA degradation was increased under AF357425/SNORD113-6 inhibition in both murine and human primary fibroblasts, but effects on protein expression were more ambiguous. Integrin signalling is crucial for cell-cell and cell-matrix interactions, and correspondingly, we observed altered human primary arterial fibroblast function upon SNORD113-6 inhibition.
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Affiliation(s)
- Eva van Ingen
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Daphne A L van den Homberg
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - M Leontien van der Bent
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Hailiang Mei
- Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Veerle Kremer
- Department of Physiology, Amsterdam Cardiovascular Sciences, Vrije Universiteit, Amsterdam UMC location VUMC, Amsterdam, The Netherlands
| | - Reinier A Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences, Vrije Universiteit, Amsterdam UMC location VUMC, Amsterdam, The Netherlands
- Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
- German Center for Cardiovascular Research (DZHK), Frankfurt am Main, Germany
| | - Paul H A Quax
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Johann Wojta
- Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria
| | - A Yaël Nossent
- Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
- Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
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Han C, Sun LY, Luo XQ, Pan Q, Sun YM, Zeng ZC, Chen TQ, Huang W, Fang K, Wang WT, Chen YQ. Chromatin-associated orphan snoRNA regulates DNA damage-mediated differentiation via a non-canonical complex. Cell Rep 2022; 38:110421. [PMID: 35354054 DOI: 10.1016/j.celrep.2022.110421] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 10/04/2021] [Accepted: 01/31/2022] [Indexed: 12/21/2022] Open
Abstract
Small nucleolar RNAs (snoRNAs) are commonly acknowledged as a class of homogeneous non-coding RNAs that guide ribosomal RNA modifications. However, snoRNAs referred to as orphans have largely unknown functions. Here, we systematically profile chromatin-associated snoRNAs (casnoRNAs) in mammalian cells and identify a subgroup of orphan casnoRNAs responding to DNA damage stress, among which SNORA73 shows the most marked reduction in chromatin enrichment. Downregulated SNORA73 maintains cancer genome stability and differentiation block in hematopoietic malignancy. Mechanistically, casnoRNA the 5' end non-canonical structure of SNORA73 is critical for its function and binding to poly (ADP-ribose) polymerase 1 (PARP1). SNORA73 inhibits PARP1 auto-PARylation to affect cancer genome stability by forming a small nucleolar ribonucleoprotein (snoRNP) with PARP1 and canonical H/ACA proteins DKC1/NHP2. Our findings reveal the role of an orphan snoRNA serving as casnoRNA and highlights a link between non-canonical structure of snoRNA and their functional diversity.
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Affiliation(s)
- Cai Han
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Lin-Yu Sun
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Xue-Qun Luo
- The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Qi Pan
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Yu-Meng Sun
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Zhan-Cheng Zeng
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Tian-Qi Chen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Wei Huang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Ke Fang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Wen-Tao Wang
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
| | - Yue-Qin Chen
- MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
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Alvarado-Hernandez B, Ma Y, Sharma NR, Majerciak V, Lobanov A, Cam M, Zhu J, Zheng ZM. Protein-RNA Interactome Analysis Reveals Wide Association of Kaposi's Sarcoma-Associated Herpesvirus ORF57 with Host Noncoding RNAs and Polysomes. J Virol 2022; 96:e0178221. [PMID: 34787459 PMCID: PMC8826805 DOI: 10.1128/jvi.01782-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/07/2021] [Indexed: 12/15/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 is an RNA-binding posttranscriptional regulator. We recently applied an affinity-purified anti-ORF57 antibody to conduct ORF57 cross-linking immunoprecipitation (CLIP) in combination with RNA-sequencing (CLIP-seq) and analyzed the genome-wide host RNA transcripts in association with ORF57 in BCBL-1 cells with lytic KSHV infection. Mapping of the CLIP RNA reads to the human genome (GRCh37) revealed that most of the ORF57-associated RNA reads were from rRNAs. The remaining RNA reads mapped to several classes of host noncoding and protein-coding mRNAs. We found that ORF57 binds and regulates expression of a subset of host long noncoding RNAs (lncRNAs), including LINC00324, LINC00355, and LINC00839, which are involved in cell growth. ORF57 binds small nucleolar RNAs (snoRNAs) responsible for 18S and 28S rRNA modifications but does not interact with fibrillarin or NOP58. We validated ORF57 interactions with 67 snoRNAs by ORF57 RNA immunoprecipitation (RIP)-snoRNA array assays. Most of the identified ORF57 rRNA binding sites (BS) overlap the sites binding snoRNAs. We confirmed ORF57-snoRA71B RNA interaction in BCBL-1 cells by ORF57 RIP and Northern blot analyses using a 32P-labeled oligonucleotide probe from the 18S rRNA region complementary to snoRA71B. Using RNA oligonucleotides from the rRNA regions that ORF57 binds for oligonucleotide pulldown-Western blot assays, we selectively verified ORF57 interactions with 5.8S and 18S rRNAs. Polysome profiling revealed that ORF57 associates with both monosomes and polysomes and that its association with polysomes increases PABPC1 binding to polysomes but prevents Ago2 association with polysomes. Our data indicate a functional correlation with ORF57 binding and suppression of Ago2 activities for ORF57 promotion of gene expression. IMPORTANCE As an RNA-binding protein, KSHV ORF57 regulates RNA splicing, stability, and translation and inhibits host innate immunity by blocking the formation of RNA granules in virus-infected cells. In this study, ORF57 was found to interact with many host noncoding RNAs, including lncRNAs, snoRNAs, and rRNAs, to carry out additional unknown functions. ORF57 binds a group of lncRNAs via the RNA motifs identified by ORF57 CLIP-seq to regulate their expression. ORF57 associates with snoRNAs independently of fibrillarin and NOP58 proteins and with rRNA in the regions that commonly bind snoRNAs. Knockdown of fibrillarin expression decreases the expression of snoRNAs and CDK4 but does not affect viral gene expression. More importantly, we found that ORF57 binds translationally active polysomes and enhances PABPC1 but prevents Ago2 association with polysomes. Data provide compelling evidence on how ORF57 in KSHV-infected cells might regulate protein synthesis by blocking Ago2's hostile activities on translation.
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Affiliation(s)
- Beatriz Alvarado-Hernandez
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Yanping Ma
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Nishi R. Sharma
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Vladimir Majerciak
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
| | - Alexei Lobanov
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, NCI/NIH, Bethesda, Maryland, USA
| | - Maggie Cam
- CCR Collaborative Bioinformatics Resource, Center for Cancer Research, NCI/NIH, Bethesda, Maryland, USA
| | - Jun Zhu
- Genome Technology Laboratory, System Biology Center, NHLBI/NIH, Bethesda, Maryland, USA
| | - Zhi-Ming Zheng
- Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, NCI/NIH, Frederick, Maryland, USA
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38
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Fractional 2'-O-methylation in the ribosomal RNA of Dictyostelium discoideum supports ribosome heterogeneity in Amoebozoa. Sci Rep 2022; 12:1952. [PMID: 35121764 PMCID: PMC8817022 DOI: 10.1038/s41598-022-05447-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/07/2022] [Indexed: 12/02/2022] Open
Abstract
A hallmark of ribosomal RNA (rRNA) are 2′-O-methyl groups that are introduced sequence specifically by box C/D small nucleolar RNAs (snoRNAs) in ribonucleoprotein particles. Most data on this chemical modification and its impact on RNA folding and stability are derived from organisms of the Opisthokonta supergroup. Using bioinformatics and RNA-seq data, we identify 30 novel box C/D snoRNAs in Dictyostelium discoideum, many of which are differentially expressed during the multicellular development of the amoeba. By applying RiboMeth-seq, we find 49 positions in the 17S and 26S rRNA 2′-O-methylated. Several of these nucleotides are substoichiometrically modified, with one displaying dynamic modification levels during development. Using homology-based models for the D. discoideum rRNA secondary structures, we localize many modified nucleotides in the vicinity of the ribosomal A, P and E sites. For most modified positions, a guiding box C/D snoRNA could be identified, allowing to determine idiosyncratic features of the snoRNA/rRNA interactions in the amoeba. Our data from D. discoideum represents the first evidence for ribosome heterogeneity in the Amoebozoa supergroup, allowing to suggest that it is a common feature of all eukaryotes.
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Lin Q, Shi Y, Liu Z, Mehrpour M, Hamaï A, Gong C. Non-coding RNAs as new autophagy regulators in cancer progression. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166293. [PMID: 34688868 DOI: 10.1016/j.bbadis.2021.166293] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 09/17/2021] [Accepted: 10/10/2021] [Indexed: 12/09/2022]
Abstract
Recent advances highlight that non-coding RNAs (ncRNAs) are emerging as fundamental regulators in various physiological as well as pathological processes by regulating macro-autophagy. Studies have disclosed that macro-autophagy, which is a highly conserved process involving cellular nutrients, components, and recycling of organelles, can be either selective or non-selective and ncRNAs show their regulation on selective autophagy as well as non-selective autophagy. The abnormal expression of ncRNAs will result in the impairment of autophagy and contribute to carcinogenesis and cancer progression by regulating both selective autophagy as well as non-selective autophagy. This review focuses on the regulatory roles of ncRNAs in autophagy and their involvement in cancer which may provide valuable therapeutic targets for cancer management.
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Affiliation(s)
- Qun Lin
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China
| | - Yu Shi
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China
| | - Zihao Liu
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China
| | - Maryam Mehrpour
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, 75993, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France
| | - Ahmed Hamaï
- Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, 75993, Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75993 Paris, France
| | - Chang Gong
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Bioland Laboratory, 510005 Guangzhou, China.
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Barros-Silva D, Klavert J, Jenster G, Jerónimo C, Lafontaine DLJ, Martens-Uzunova ES. The role of OncoSnoRNAs and Ribosomal RNA 2'-O-methylation in Cancer. RNA Biol 2021; 18:61-74. [PMID: 34775914 PMCID: PMC8677010 DOI: 10.1080/15476286.2021.1991167] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Ribosomes are essential nanomachines responsible for all protein production in cells. Ribosome biogenesis and function are energy costly processes, they are tightly regulated to match cellular needs. In cancer, major pathways that control ribosome biogenesis and function are often deregulated to ensure cell survival and to accommodate the continuous proliferation of tumour cells. Ribosomal RNAs (rRNAs) are abundantly modified with 2'-O-methylation (Nm, ribomethylation) being one of the most common modifications. In eukaryotic ribosomes, ribomethylation is performed by the methyltransferase Fibrillarin guided by box C/D small nucleolar RNAs (snoRNAs). Accumulating evidences indicate that snoRNA expression and ribosome methylation profiles are altered in cancer. Here we review our current knowledge on differential snoRNA expression and rRNA 2ʹ-O methylation in the context of human malignancies, and discuss the consequences and opportunities for cancer diagnostics, prognostics, and therapeutics.
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Affiliation(s)
- Daniela Barros-Silva
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands.,Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal
| | - Jonathan Klavert
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Guido Jenster
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), Porto, Portugal.,Department of Pathology and Molecular Immunology, School of Medicine & Biomedical Sciences, University of Porto (Icbas-up), Porto, Portugal
| | - Denis L J Lafontaine
- Rna Molecular Biology, Fonds De La Recherche Scientifique (F.r.s./fnrs), Université Libre De Bruxelles (Ulb), BioPark Campus, Gosselies, Belgium
| | - Elena S Martens-Uzunova
- Department of Urology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
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Small nucleolar RNA is potential as a novel player in leukemogenesis and clinical application. BLOOD SCIENCE 2021; 3:122-131. [PMID: 35402848 PMCID: PMC8975097 DOI: 10.1097/bs9.0000000000000091] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 09/21/2021] [Indexed: 12/19/2022] Open
Abstract
Lack of clarity of the mechanisms that underlie leukemogenesis obstructs the diagnosis, prognosis, and treatment of leukemia. Research has found that small nuclear RNA (snoRNA) plays an essential role in leukemia. These small non-coding RNAs are involved in ribosome biogenesis, including the 2′-O-methylation and pseudouridylation of precursor ribosomal RNA (pre-rRNA), and pre-rRNA splicing. Recently, many snoRNAs were found to be orphans that have no predictable RNA modification targets, but these RNAs have always been found to be located in different subcellular organelles, and they play diverse roles. Using high-throughput technology, snoRNA expression profiles have been revealed in leukemia, and some of the deregulated snoRNAs may regulate the cell cycle, differentiation, proliferation, and apoptosis in leukemic cells and confer drug resistance during leukemia treatment. In this review, we discuss the expression profiles and functions of snoRNAs, particularly orphan snoRNAs, in leukemia. It is possible that the dysregulated snoRNAs are promising diagnosis and prognosis markers for leukemia, which may serve as potential therapeutic targets in leukemia treatment.
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Emerging Functions for snoRNAs and snoRNA-Derived Fragments. Int J Mol Sci 2021; 22:ijms221910193. [PMID: 34638533 PMCID: PMC8508363 DOI: 10.3390/ijms221910193] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/16/2021] [Accepted: 09/16/2021] [Indexed: 12/11/2022] Open
Abstract
The widespread implementation of mass sequencing has revealed a diverse landscape of small RNAs derived from larger precursors. Whilst many of these are likely to be byproducts of degradation, there are nevertheless metabolically stable fragments derived from tRNAs, rRNAs, snoRNAs, and other non-coding RNA, with a number of examples of the production of such fragments being conserved across species. Coupled with specific interactions to RNA-binding proteins and a growing number of experimentally reported examples suggesting function, a case is emerging whereby the biological significance of small non-coding RNAs extends far beyond miRNAs and piRNAs. Related to this, a similarly complex picture is emerging of non-canonical roles for the non-coding precursors, such as for snoRNAs that are also implicated in such areas as the silencing of gene expression and the regulation of alternative splicing. This is in addition to a body of literature describing snoRNAs as an additional source of miRNA-like regulators. This review seeks to highlight emerging roles for such non-coding RNA, focusing specifically on “new” roles for snoRNAs and the small fragments derived from them.
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Fafard-Couture É, Bergeron D, Couture S, Abou-Elela S, Scott MS. Annotation of snoRNA abundance across human tissues reveals complex snoRNA-host gene relationships. Genome Biol 2021; 22:172. [PMID: 34088344 PMCID: PMC8176728 DOI: 10.1186/s13059-021-02391-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 05/26/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Small nucleolar RNAs (snoRNAs) are mid-size non-coding RNAs required for ribosomal RNA modification, implying a ubiquitous tissue distribution linked to ribosome synthesis. However, increasing numbers of studies identify extra-ribosomal roles of snoRNAs in modulating gene expression, suggesting more complex snoRNA abundance patterns. Therefore, there is a great need for mapping the snoRNome in different human tissues as the blueprint for snoRNA functions. RESULTS We used a low structure bias RNA-Seq approach to accurately quantify snoRNAs and compare them to the entire transcriptome in seven healthy human tissues (breast, ovary, prostate, testis, skeletal muscle, liver, and brain). We identify 475 expressed snoRNAs categorized in two abundance classes that differ significantly in their function, conservation level, and correlation with their host gene: 390 snoRNAs are uniformly expressed and 85 are enriched in the brain or reproductive tissues. Most tissue-enriched snoRNAs are embedded in lncRNAs and display strong correlation of abundance with them, whereas uniformly expressed snoRNAs are mostly embedded in protein-coding host genes and are mainly non- or anticorrelated with them. Fifty-nine percent of the non-correlated or anticorrelated protein-coding host gene/snoRNA pairs feature dual-initiation promoters, compared to only 16% of the correlated non-coding host gene/snoRNA pairs. CONCLUSIONS Our results demonstrate that snoRNAs are not a single homogeneous group of housekeeping genes but include highly regulated tissue-enriched RNAs. Indeed, our work indicates that the architecture of snoRNA host genes varies to uncouple the host and snoRNA expressions in order to meet the different snoRNA abundance levels and functional needs of human tissues.
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Affiliation(s)
- Étienne Fafard-Couture
- Département de biochimie et de génomique fonctionnelle, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1E 4 K8, Canada
| | - Danny Bergeron
- Département de biochimie et de génomique fonctionnelle, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1E 4 K8, Canada
| | - Sonia Couture
- Département de microbiologie et d'infectiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1E 4 K8, Canada
| | - Sherif Abou-Elela
- Département de microbiologie et d'infectiologie, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1E 4 K8, Canada.
| | - Michelle S Scott
- Département de biochimie et de génomique fonctionnelle, Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Québec, J1E 4 K8, Canada.
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Hayward RJ, Humphrys MS, Huston WM, Myers GSA. Dual RNA-seq analysis of in vitro infection multiplicity and RNA depletion methods in Chlamydia-infected epithelial cells. Sci Rep 2021; 11:10399. [PMID: 34001998 PMCID: PMC8128910 DOI: 10.1038/s41598-021-89921-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022] Open
Abstract
Dual RNA-seq experiments examining viral and bacterial pathogens are increasing, but vary considerably in their experimental designs, such as infection rates and RNA depletion methods. Here, we have applied dual RNA-seq to Chlamydia trachomatis infected epithelial cells to examine transcriptomic responses from both organisms. We compared two time points post infection (1 and 24 h), three multiplicity of infection (MOI) ratios (0.1, 1 and 10) and two RNA depletion methods (rRNA and polyA). Capture of bacterial-specific RNA were greatest when combining rRNA and polyA depletion, and when using a higher MOI. However, under these conditions, host RNA capture was negatively impacted. Although it is tempting to use high infection rates, the implications on host cell survival, the potential reduced length of infection cycles and real world applicability should be considered. This data highlights the delicate nature of balancing host-pathogen RNA capture and will assist future transcriptomic-based studies to achieve more specific and relevant infection-related biological insights.
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Affiliation(s)
- Regan J Hayward
- The iThree Institute, Faculty of Science, University of Technology Sydney, Sydney, Australia.
- Helmholtz Centre for Infection Research (HZI), Helmholtz Institute for RNA-based Infection Research (HIRI), Würzburg, Germany.
| | - Michael S Humphrys
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Wilhelmina M Huston
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia
| | - Garry S A Myers
- The iThree Institute, Faculty of Science, University of Technology Sydney, Sydney, Australia
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, Australia
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Baldini L, Charpentier B, Labialle S. Emerging Data on the Diversity of Molecular Mechanisms Involving C/D snoRNAs. Noncoding RNA 2021; 7:ncrna7020030. [PMID: 34066559 PMCID: PMC8162545 DOI: 10.3390/ncrna7020030] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/15/2022] Open
Abstract
Box C/D small nucleolar RNAs (C/D snoRNAs) represent an ancient family of small non-coding RNAs that are classically viewed as housekeeping guides for the 2′-O-methylation of ribosomal RNA in Archaea and Eukaryotes. However, an extensive set of studies now argues that they are involved in mechanisms that go well beyond this function. Here, we present these pieces of evidence in light of the current comprehension of the molecular mechanisms that control C/D snoRNA expression and function. From this inventory emerges that an accurate description of these activities at a molecular level is required to let the snoRNA field enter in a second age of maturity.
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Affiliation(s)
| | - Bruno Charpentier
- Correspondence: (B.C.); (S.L.); Tel.: +33-3-72-74-66-27 (B.C.); +33-3-72-74-66-51 (S.L.)
| | - Stéphane Labialle
- Correspondence: (B.C.); (S.L.); Tel.: +33-3-72-74-66-27 (B.C.); +33-3-72-74-66-51 (S.L.)
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Oncogenic SNORD12B activates the AKT-mTOR-4EBP1 signaling in esophageal squamous cell carcinoma via nucleus partitioning of PP-1α. Oncogene 2021; 40:3734-3747. [PMID: 33941854 DOI: 10.1038/s41388-021-01809-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 04/06/2021] [Accepted: 04/20/2021] [Indexed: 02/03/2023]
Abstract
Esophageal cancer is a complex malignancy and the sixth leading cause of cancer death worldwide. In Eastern Asia including China, about 90% of all incident cases have esophageal squamous cell carcinoma (ESCC). Mounting evidence elucidates that aberrant expression of various non-coding RNAs (ncRNAs) contributes to ESCC progression, but it remains unclear how small nucleolar RNAs (snoRNAs) are involved in ESCC development. We systemically screened clinically relevant snoRNAs in ESCC via integrative analyses of The Cancer Genome Atlas (TCGA) data and validation in ESCC tissues. We found that snoRNA SNORD12B was one of the most evidently upregulated snoRNAs in ESCC specimens and its high expression was significantly associated with poor prognosis of patients. SNORD12B profoundly promoted proliferation, migration, invasion, and metastasis of ESCC cells in vitro and in vivo, indicating its oncogene nature. In particular, SNORD12B could interact with PP-1α, one of the three catalytic subunits of serine/threonine protein phosphatase 1, which is a major phosphatase that directly dephosphorylates AKT to suppress its activation. Interestingly, high levels of SNORD12B in ESCC cells could break interactions between 14-3-3ζ and PP-1α, abolish the retention of PP-1α in the cytosol by 14-3-3ζ and relocate PP-1α from the cytosol to the nucleus. This led to sequestered PP-1α in the nucleus, enhanced phosphorylation of AKT in the cytosol, activated AKT-mTOR-4EBP1 signaling, and, thus, ESCC progression. These insights would improve our understanding of how snoRNAs contribute to tumorigenesis and highlight the potential of snoRNAs as future therapeutic targets against cancers.
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Dong W, Liu X, Yang C, Wang D, Xue Y, Ruan X, Zhang M, Song J, Cai H, Zheng J, Liu Y. Glioma glycolipid metabolism: MSI2-SNORD12B-FIP1L1-ZBTB4 feedback loop as a potential treatment target. Clin Transl Med 2021; 11:e411. [PMID: 34047477 PMCID: PMC8114150 DOI: 10.1002/ctm2.411] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/13/2021] [Accepted: 04/19/2021] [Indexed: 12/26/2022] Open
Abstract
Abnormal energy metabolism, including enhanced aerobic glycolysis and lipid synthesis, is a well-established feature of glioblastoma (GBM) cells. Thus, targeting the cellular glycolipid metabolism can be a feasible therapeutic strategy for GBM. This study aimed to evaluate the roles of MSI2, SNORD12B, and ZBTB4 in regulating the glycolipid metabolism and proliferation of GBM cells. MSI2 and SNORD12B expression was significantly upregulated and ZBTB4 expression was significantly low in GBM tissues and cells. Knockdown of MSI2 or SNORD12B or overexpression of ZBTB4 inhibited GBM cell glycolipid metabolism and proliferation. MSI2 may improve SNORD12B expression by increasing its stability. Importantly, SNORD12B increased utilization of the ZBTB4 mRNA transcript distal polyadenylation signal in alternative polyadenylation processing by competitively combining with FIP1L1, which decreased ZBTB4 expression because of the increased proportion of the 3' untranslated region long transcript. ZBTB4 transcriptionally suppressed the expression of HK2 and ACLY by binding directly to the promoter regions. Additionally, ZBTB4 bound the MSI promoter region to transcriptionally suppress MSI2 expression, thereby forming an MSI2/SNORD12B/FIP1L1/ZBTB4 feedback loop to regulate the glycolipid metabolism and proliferation of GBM cells. In conclusion, MSI2 increased the stability of SNORD12B, which regulated ZBTB4 alternative polyadenylation processing by competitively binding to FIP1L1. Thus, the MSI2/SNORD12B/FIP1L1/ZBTB4 positive feedback loop plays a crucial role in regulating the glycolipid metabolism of GBM cells and provides a potential drug target for glioma treatment.
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Affiliation(s)
- Weiwei Dong
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
| | - Xiaobai Liu
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
| | - Chunqing Yang
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
| | - Di Wang
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
| | - Yixue Xue
- Department of Neurobiology, School of Life SciencesChina Medical UniversityShenyangChina
- Key Laboratory of Cell Biology, Ministry of Public Health of ChinaChina Medical UniversityShenyangChina
- Key Laboratory of Medical Cell Biology, Ministry of Education of ChinaChina Medical UniversityShenyangChina
| | - Xuelei Ruan
- Department of Neurobiology, School of Life SciencesChina Medical UniversityShenyangChina
- Key Laboratory of Cell Biology, Ministry of Public Health of ChinaChina Medical UniversityShenyangChina
- Key Laboratory of Medical Cell Biology, Ministry of Education of ChinaChina Medical UniversityShenyangChina
| | - Mengyang Zhang
- Department of Neurobiology, School of Life SciencesChina Medical UniversityShenyangChina
- Key Laboratory of Cell Biology, Ministry of Public Health of ChinaChina Medical UniversityShenyangChina
- Key Laboratory of Medical Cell Biology, Ministry of Education of ChinaChina Medical UniversityShenyangChina
| | - Jian Song
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
| | - Heng Cai
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
| | - Jian Zheng
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
| | - Yunhui Liu
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangChina
- Key Laboratory of Neuro‐oncology in Liaoning ProvinceShenyangChina
- Liaoning Province Medical Surgery and Rehabilitation Robot Technology Engineering Research CenterShenyangChina
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Yoon Y, Soles LV, Shi Y. PAS-seq 2: A fast and sensitive method for global profiling of polyadenylated RNAs. Methods Enzymol 2021; 655:25-35. [PMID: 34183125 PMCID: PMC11651360 DOI: 10.1016/bs.mie.2021.03.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Alternative polyadenylation (APA) is a widespread phenomenon in eukaryotes that contributes to regulating gene expression and generating proteomic diversity. APA plays critical roles in development and its mis-regulation has been implicated in a wide variety of human diseases, including cancer. To study APA on the transcriptome-wide level, numerous deep sequencing methods that capture 3' end of mRNAs have been developed in the past decade, but they generally require a large amount of hands-on time and/or high RNA input. Here, we introduce PAS-seq 2, a fast and sensitive method for global and quantitative profiling of polyadenylated RNAs. Compared to our original PAS-seq, this method takes less time and requires much lower total RNA input due to improvement in the reverse transcription process. PAS-seq 2 can be applied to both APA and differential gene expression analyses.
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Affiliation(s)
- Yoseop Yoon
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, United States
| | - Lindsey V Soles
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, United States
| | - Yongsheng Shi
- Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, United States.
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Breuer R, Gomes-Filho JV, Randau L. Conservation of Archaeal C/D Box sRNA-Guided RNA Modifications. Front Microbiol 2021; 12:654029. [PMID: 33776983 PMCID: PMC7994747 DOI: 10.3389/fmicb.2021.654029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 02/19/2021] [Indexed: 12/18/2022] Open
Abstract
Post-transcriptional modifications fulfill many important roles during ribosomal RNA maturation in all three domains of life. Ribose 2'-O-methylations constitute the most abundant chemical rRNA modification and are, for example, involved in RNA folding and stabilization. In archaea, these modification sites are determined by variable sets of C/D box sRNAs that guide the activity of the rRNA 2'-O-methyltransferase fibrillarin. Each C/D box sRNA contains two guide sequences that can act in coordination to bridge rRNA sequences. Here, we will review the landscape of archaeal C/D box sRNA genes and their target sites. One focus is placed on the apparent accelerated evolution of guide sequences and the varied pairing of the two individual guides, which results in different rRNA modification patterns and RNA chaperone activities.
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Affiliation(s)
| | | | - Lennart Randau
- Prokaryotic RNA Biology, Philipps-Universität Marburg, Marburg, Germany
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50
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Wang S, Guo N, Li S, He Y, Zheng D, Li L, Wang Z. EZH2 Dynamically Associates With Non-coding RNAs in Mouse Hearts After Acute Angiotensin II Treatment. Front Cardiovasc Med 2021; 8:585691. [PMID: 33732733 PMCID: PMC7959742 DOI: 10.3389/fcvm.2021.585691] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 02/01/2021] [Indexed: 12/15/2022] Open
Abstract
Enhancer of zeste 2 (EZH2) governs gene reprogramming during cardiac hypertrophy through epigenetic remodeling, a process regulated by numerous non-coding RNAs (ncRNAs). However, the dynamic interaction between EZH2 and ncRNAs upon hypertrophic stimulation remains elusive. Here we performed an unbiased profiling for EZH2-associated ncRNAs in mouse hearts treated with Angiotensin II (AngII) at different time points (0, 4, and 24 h). The interactions between EZH2 and long ncRNAs (lncRNAs), Chaer, Mirt1, Hotair, and H19, were validated by PCR. RIP-seq analysis identified a total of 126 ncRNAs to be significantly associated with EZH2. These ncRNAs covers all five categories including intergenic, antisense, intron-related, promoter-related and both antisense and promoter-related. According to their changing patterns after AngII treatment, these ncRNAs were clustered into four groups, constantly enhanced, transiently enhanced, constantly suppressed and transiently suppressed. Structural prediction showed that EZH2 bound to hairpin motifs in ncRNAs including snoRNAs. Interaction strength prediction and RNA pull-down assay confirmed the direct interaction between EZH2 and Snora33. Interestingly, two antisense lncRNAs of Malat1, Gm20417, and Gm37376, displayed different binding patterns from their host gene after AngII treatment, suggesting a crucial role of this genomic locus in modulating EZH2 behavior. Our findings reveal the profile of EZH2-associated ncRNAs upon hypertrophic stimulation, and imply a dynamic regulation of EZH2 function in cardiac hypertrophy.
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Affiliation(s)
- Shun Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ningning Guo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shuangling Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuan He
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Di Zheng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lili Li
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhihua Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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