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1
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Zhang M, Lu Z. tRNA modifications: greasing the wheels of translation and beyond. RNA Biol 2025; 22:1-25. [PMID: 39723662 DOI: 10.1080/15476286.2024.2442856] [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] [Revised: 11/29/2024] [Accepted: 12/11/2024] [Indexed: 12/28/2024] Open
Abstract
Transfer RNA (tRNA) is one of the most abundant RNA types in cells, acting as an adaptor to bridge the genetic information in mRNAs with the amino acid sequence in proteins. Both tRNAs and small fragments processed from them play many nonconventional roles in addition to translation. tRNA molecules undergo various types of chemical modifications to ensure the accuracy and efficiency of translation and regulate their diverse functions beyond translation. In this review, we discuss the biogenesis and molecular mechanisms of tRNA modifications, including major tRNA modifications, writer enzymes, and their dynamic regulation. We also summarize the state-of-the-art technologies for measuring tRNA modification, with a particular focus on 2'-O-methylation (Nm), and discuss their limitations and remaining challenges. Finally, we highlight recent discoveries linking dysregulation of tRNA modifications with genetic diseases.
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Affiliation(s)
- Minjie Zhang
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Medical Epigenetics, Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Zhipeng Lu
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
- Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA, USA
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2
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Hu Y, Chen C, Lin K, Tong X, Huang T, Qiu T, Chen X, Xu J, Xie W, Sun X, Feng S, Lu M, Zhao Z, Chen X, Xue X, Shen X. NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB-STAT3 signalling in a non-m5C manner. Clin Transl Med 2025; 15:e70282. [PMID: 40156167 PMCID: PMC11953055 DOI: 10.1002/ctm2.70282] [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: 10/01/2024] [Revised: 03/03/2025] [Accepted: 03/15/2025] [Indexed: 04/01/2025] Open
Abstract
NSUN2, a major methyltransferase that catalyzes m5C methylation in eukaryotes, is known to be implicated in the development of multiple cancers. However, its role in colorectal cancer (CRC) and the related molecular mechanisms have yet to be sufficiently determined. Here, we conducted an analysis of public database (722 CRC patients) and two distinct cohorts from our centre (1559 CRC patients), which revealed that NSUN2 is upregulated in CRC and correlates with unfavourable prognosis. Our analyses also showed that NSUN2 promotes the proliferation and metastasis capabilities of CRC cells. Intriguingly, NSUN2 was found to promote CRC via an m5C-independent mechanism, which has not been previously reported. Overexpression of both wild-type and m5C enzymatic-dead mutant NSUN2 upregulated and activated the ErbB-STAT3 signalling pathway. We also found that both wild-type and the m5C enzymatic-dead mutant NSUN2 closely interacted with CUL4B. Silencing of CUL4B effectively inhibited the m5C-independent function of NSUN2. Moreover, overexpression of NSUN2 enhanced the sensitivity of CRC cells to lapatinib. Taken together, our findings revealed a novel m5C-independent mechanism for NSUN2 in the malignancy and lapatinib sensitivity of CRC via activation of the CUL4B/ErbB-STAT3 pathway, which provides a potential therapeutic strategy for patients with CRC. HIGHLIGHTS: NSUN2 is upregulated in CRC and associated with poor prognosis of CRC patients. NSUN2 promotes CRC malignancy independently of its m5C-enzymatic activity, a mechanism that has not been previously reported. The non-m5C carcinogenic roles of NSUN2 may be mediated through interactions with CUL4B, thereby activating the ErbB-STAT3 signalling pathway. NSUN2-mediated upregulation of ErbB-STAT3 pathway enhances the sensitivity of CRC to lapatinib treatment.
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Affiliation(s)
- Yuanbo Hu
- Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of General SurgeryThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Chenbin Chen
- Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Kezhi Lin
- Experiemtial Center of Basic Medicine, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Xinya Tong
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Tingting Huang
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
- Department of Obstetrics and Gynecology, Maternal and Child Care Service HospitalYueqingChina
| | - Tianle Qiu
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Xietao Chen
- Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Jun Xu
- Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Wangkai Xie
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Xiangwei Sun
- Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Shiyu Feng
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Mingdong Lu
- Department of General SurgeryThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Zhiguang Zhao
- Department of PathologyThe Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Xiaodong Chen
- Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Xiangyang Xue
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical SciencesWenzhou Medical UniversityWenzhouChina
| | - Xian Shen
- Department of General SurgeryThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
- Department of General SurgeryThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and TranslationThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina
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Gonskikh Y, Tirrito C, Bommisetti P, Mendoza-Figueroa M, Stoute J, Kim J, Wang Q, Song Y, Liu K. Spatial regulation of NSUN2-mediated tRNA m5C installation in cognitive function. Nucleic Acids Res 2025; 53:gkae1169. [PMID: 39673800 PMCID: PMC11754655 DOI: 10.1093/nar/gkae1169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 10/30/2024] [Accepted: 12/12/2024] [Indexed: 12/16/2024] Open
Abstract
Enzyme-mediated modifications of tRNA, such as 5-methylcytosine (m5C) installed by nuclear-enriched NOP2/Sun RNA methyltransferase 2 (NSUN2), play a critical role in neuronal development and function. However, our understanding of these modifications' spatial installation and biological functions remains incomplete. In this study, we demonstrate that a nucleoplasm-localized G679R NSUN2 mutant, linked to intellectual disability, diminishes NSUN2-mediated tRNA m5C in human cell lines and Drosophila. Our findings indicate that inability of G679R-NSUN2 to install m5C is primarily attributed to its reduced binding to tRNA rather than its nucleoplasmic localization. Conversely, an NSUN2 variant lacking an internal intrinsically disordered region (ΔIDR-NSUN2) can install ∼80% m5C within the nucleoplasm. Furthermore, we show that tRNA m5C levels are positively correlated to cognitive performance in Drosophila, where expressing G679R-NSUN2 leads to the most severe social behavioral deficits while expressing ΔIDR-NSUN2 results in less pronounced deficits. This work illuminates the molecular mechanism underlying G679R disease mutation in cognitive function and offers valuable insights into the significance of the cellular localization of m5C installation on tRNA for neuronal function.
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Affiliation(s)
- Yulia Gonskikh
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Christian Tirrito
- Biology Graduate Group, University of Pennsylvania, School of Arts and Sciences, Philadelphia, PA 19104, USA
- The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Praneeth Bommisetti
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Maria Saraí Mendoza-Figueroa
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Julian Stoute
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joshua Kim
- The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Qin Wang
- The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Yuanquan Song
- The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kathy Fange Liu
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
- Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA 19104, USA
- Penn Center for Genome Integrity, University of Pennsylvania, Philadelphia, PA 19104, USA
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Miao W, Porter D, Li Y, Meservey L, Yang YY, Ma C, Ferguson I, Tien V, Jack T, Ducoli L, Lopez-Pajares V, Tao S, Savage P, Wang Y, Khavari P. Glucose binds and activates NSUN2 to promote translation and epidermal differentiation. Nucleic Acids Res 2024; 52:13577-13593. [PMID: 39565212 PMCID: PMC11662651 DOI: 10.1093/nar/gkae1097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 09/16/2024] [Accepted: 10/25/2024] [Indexed: 11/21/2024] Open
Abstract
Elevations in intracellular glucose concentrations are essential for epithelial cell differentiation by mechanisms that are not fully understood. Glucose has recently been found to directly bind several proteins to alter their functions to enhance differentiation. Among the newly identified glucose-binding proteins is NSUN2, an RNA-binding protein that we identified as indispensable for epidermal differentiation. Glucose was found to bind conserved sequences within NSUN2, enhancing its binding to S-adenosyl-L-methionine and boosting its enzymatic activity. Additionally, glucose enhanced NSUN2's proximity to proteins involved in mRNA translation, with NSUN2 modulating global messenger RNA (mRNA) translation, particularly that of key pro-differentiation mRNAs containing m5C modifications, such as GRHL3. Glucose thus engages diverse molecular mechanisms beyond its energetic roles to facilitate cellular differentiation processes.
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Affiliation(s)
- Weili Miao
- Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Dr, Stanford, CA 94305, USA
| | - Douglas F Porter
- Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Dr, Stanford, CA 94305, USA
| | - Ya Li
- Department of Chemistry, University of California, 501 Big Springs Road, Riverside, CA 92521, USA
| | - Lindsey M Meservey
- Department of Biology, Stanford University, 371 Jane Stanford Way, Stanford, CA 94305, USA
| | - Yen-Yu Yang
- Department of Chemistry, University of California, 501 Big Springs Road, Riverside, CA 92521, USA
| | - Chengjie Ma
- Department of Chemistry, University of California, 501 Big Springs Road, Riverside, CA 92521, USA
| | - Ian D Ferguson
- Program in Cancer Biology, Stanford University, 265 Campus Drive, Stanford, CA 94305, USA
| | - Vivian B Tien
- Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Dr, Stanford, CA 94305, USA
| | - Timothy M Jack
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84604, USA
| | - Luca Ducoli
- Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Dr, Stanford, CA 94305, USA
| | - Vanessa Lopez-Pajares
- Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Dr, Stanford, CA 94305, USA
| | - Shiying Tao
- Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Dr, Stanford, CA 94305, USA
| | - Paul B Savage
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84604, USA
| | - Yinsheng Wang
- Department of Chemistry, University of California, 501 Big Springs Road, Riverside, CA 92521, USA
| | - Paul A Khavari
- Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Dr, Stanford, CA 94305, USA
- Veterans Affairs Palo Alto Healthcare System, 3801 Miranda Ave, Palo Alto, CA 94304, USA
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Lu Y, Yang L, Feng Q, Liu Y, Sun X, Liu D, Qiao L, Liu Z. RNA 5-Methylcytosine Modification: Regulatory Molecules, Biological Functions, and Human Diseases. GENOMICS, PROTEOMICS & BIOINFORMATICS 2024; 22:qzae063. [PMID: 39340806 PMCID: PMC11634542 DOI: 10.1093/gpbjnl/qzae063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/12/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024]
Abstract
RNA methylation modifications influence gene expression, and disruptions of these processes are often associated with various human diseases. The common RNA methylation modification 5-methylcytosine (m5C), which is dynamically regulated by writers, erasers, and readers, widely occurs in transfer RNAs (tRNAs), messenger RNAs (mRNAs), ribosomal RNAs (rRNAs), enhancer RNAs (eRNAs), and other non-coding RNAs (ncRNAs). RNA m5C modification regulates metabolism, stability, nuclear export, and translation of RNA molecules. An increasing number of studies have revealed the critical roles of the m5C RNA modification and its regulators in the development, diagnosis, prognosis, and treatment of various human diseases. In this review, we summarized the recent studies on RNA m5C modification and discussed the advances in its detection methodologies, distribution, and regulators. Furthermore, we addressed the significance of RNAs modified with m5C marks in essential biological processes as well as in the development of various human disorders, from neurological diseases to cancers. This review provides a new perspective on the diagnosis, treatment, and monitoring of human diseases by elucidating the complex regulatory network of the epigenetic m5C modification.
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Affiliation(s)
- Yanfang Lu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China
| | - Liu Yang
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China
| | - Qi Feng
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China
| | - Yong Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China
| | - Xiaohui Sun
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China
| | - Dongwei Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China
| | - Long Qiao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhangsuo Liu
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou 450052, China
- Henan Province Research Center for Kidney Disease, Zhengzhou 450052, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou 450052, China
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Zhang X, Zhang Y, Li R, Li Y, Wang Q, Wang Y, Chen X, Wang W, Pang E, Li Y, Wang J, Zheng J, Zhang J. STUB1-mediated ubiquitination and degradation of NSUN2 promotes hepatocyte ferroptosis by decreasing m 5C methylation of Gpx4 mRNA. Cell Rep 2024; 43:114885. [PMID: 39453812 DOI: 10.1016/j.celrep.2024.114885] [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: 01/26/2024] [Revised: 08/01/2024] [Accepted: 10/02/2024] [Indexed: 10/27/2024] Open
Abstract
Ferroptosis is an iron-dependent cell death that occurs due to the peroxidation of phospholipids in the cell membrane. In this study, we find that the protein level of NSUN2 is significantly decreased in hepatocyte ferroptosis. This is attributed to STUB1-mediated ubiquitination of NSUN2 at lysines 457 and 654, promoting NSUN2 degradation in ferroptosis. Selenoprotein glutathione peroxidase 4 (GPX4) is a prominent suppressor of ferroptosis. We find that downregulation of NSUN2 diminishes m5C methylation of Gpx4 mRNA 3' UTR. The reduction of NSUN2-mediated Gpx4 mRNA m5C methylation abrogates the interaction between SBP2 and the selenocysteine insertion sequence (SECIS) and leads to inhibition of GPX4 protein expression. Lower GPX4 expression promotes hepatocyte ferroptosis in vivo and in vitro, which is reversed by restoration of NSUN2. These findings shed light on the mechanism of NSUN2 degradation and also indicate that the STUB1-NSUN2-GPX4 axis plays a regulatory role in hepatocyte ferroptosis.
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Affiliation(s)
- Xiaotian Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
| | - Yihua Zhang
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Rongrong Li
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yibo Li
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Qi Wang
- MOE Key Laboratory for Biodiversity Science and Ecological Engineering and Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Ying Wang
- Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xinying Chen
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Weihua Wang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Erli Pang
- MOE Key Laboratory for Biodiversity Science and Ecological Engineering and Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yanyan Li
- Center for Healthy Aging, Changzhi Medical College, Changzhi 046000, China
| | - Jia Wang
- Department of Immunology, Changzhi Medical College, Changzhi 046000, China
| | - Jinping Zheng
- Center for Healthy Aging, Changzhi Medical College, Changzhi 046000, China
| | - Junjie Zhang
- The Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Department of Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
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Wen J, Zhu Q, Liu Y, Gou LT. RNA modifications: emerging players in the regulation of reproduction and development. Acta Biochim Biophys Sin (Shanghai) 2024; 57:33-58. [PMID: 39574165 PMCID: PMC11802351 DOI: 10.3724/abbs.2024201] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 11/05/2024] [Indexed: 01/25/2025] Open
Abstract
The intricate world of RNA modifications, collectively termed the epitranscriptome, covers over 170 identified modifications and impacts RNA metabolism and, consequently, almost all biological processes. In this review, we focus on the regulatory roles and biological functions of a panel of dominant RNA modifications (including m 6A, m 5C, Ψ, ac 4C, m 1A, and m 7G) on three RNA types-mRNA, tRNA, and rRNA-in mammalian development, particularly in the context of reproduction as well as embryonic development. We discuss in detail how those modifications, along with their regulatory proteins, affect RNA processing, structure, localization, stability, and translation efficiency. We also highlight the associations among dysfunctions in RNA modification-related proteins, abnormal modification deposition and various diseases, emphasizing the roles of RNA modifications in critical developmental processes such as stem cell self-renewal and cell fate transition. Elucidating the molecular mechanisms by which RNA modifications influence diverse developmental processes holds promise for developing innovative strategies to manage developmental disorders. Finally, we outline several unexplored areas in the field of RNA modification that warrant further investigation.
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Affiliation(s)
- Junfei Wen
- Key Laboratory of RNA InnovationScience and EngineeringShanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular. Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai200031China
- University of Chinese Academy of SciencesBeijing100049China
| | - Qifan Zhu
- Key Laboratory of RNA InnovationScience and EngineeringShanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular. Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai200031China
- University of Chinese Academy of SciencesBeijing100049China
| | - Yong Liu
- Key Laboratory of RNA InnovationScience and EngineeringShanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular. Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai200031China
| | - Lan-Tao Gou
- Key Laboratory of RNA InnovationScience and EngineeringShanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular. Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai200031China
- University of Chinese Academy of SciencesBeijing100049China
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8
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Jiang X, Zhan L, Tang X. RNA modifications in physiology and pathology: Progressing towards application in clinical settings. Cell Signal 2024; 121:111242. [PMID: 38851412 DOI: 10.1016/j.cellsig.2024.111242] [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: 02/16/2024] [Revised: 05/23/2024] [Accepted: 05/30/2024] [Indexed: 06/10/2024]
Abstract
The potential to modify individual nucleotides through chemical means in order to impact the electrostatic charge, hydrophobic properties, and base pairing of RNA molecules is harnessed in the medical application of stable synthetic RNAs like mRNA vaccines and synthetic small RNA molecules. These modifications are used to either increase or decrease the production of therapeutic proteins. Additionally, naturally occurring biochemical alterations of nucleotides play a role in regulating RNA metabolism and function, thereby modulating essential cellular processes. Research elucidating the mechanisms through which RNA modifications govern fundamental cellular functions in multicellular organisms has enhanced our comprehension of how irregular RNA modification profiles can lead to human diseases. Collectively, these fundamental scientific findings have unveiled the molecular and cellular functions of RNA modifications, offering new opportunities for therapeutic intervention and paving the way for a variety of innovative clinical strategies.
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Affiliation(s)
- Xue Jiang
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China
| | - Lijuan Zhan
- College of Pharmacy and Traditional Chinese Medicine, Jiangsu College of Nursing, Huaian, Jiangsu 223005, China.
| | - Xiaozhu Tang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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9
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Lin W, Lin Z, Wu L, Zheng Y, Xi H. NSUN2 facilitates tenogenic differentiation of rat tendon-derived stem cells via m5C methylation of KLF2. Regen Ther 2024; 26:792-799. [PMID: 39309399 PMCID: PMC11415532 DOI: 10.1016/j.reth.2024.08.023] [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: 08/04/2024] [Revised: 08/26/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction Tendon-derived stem cells (TDSCs) play a critical role in tendon repair. N5-methylcytosine (m5C) is a key regulator of cellular processes such as differentiation. This study aimed to investigate the impact of m5C on TDSC differentiation and the underlying mechanism. Methods TDSCs were isolated from rats and identified, and a tendon injury rat model was generated. Tenogenic differentiation in vitro was evaluated using Sirius red staining and quantitative real-time polymerase chain reaction, while that in vivo was assessed using immunohistochemistry and hematoxylin‒eosin staining. m5C methylation was analyzed using methylated RNA immunoprecipitation, dual-luciferase reporter assay, and RNA stability assay. Results The results showed that m5C levels and NSUN2 expression were increased in TDSCs after tenogenic differentiation. Knockdown of NSUN2 inhibited m5C methylation of KLF2 and decreased its stability, which was recognized by YBX1. Moreover, interfering with KLF2 suppressed tenogenic differentiation of TDSCs, which could be abrogated by KLF2 overexpression. Additionally, TDSCs after NSUN2 overexpression contributed to ameliorating tendon injury in vivo. In conclusion, NSUN2 promotes tenogenic differentiation of TDSCs via m5C methylation of KLF2 and accelerates tendon repair. Conclusions The findings suggest that overexpression of NSUN2 can stimulate the differentiation ability of TDSCs, which can be used in the treatment of tendinopathy.
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Affiliation(s)
- Wei Lin
- Taizhou Hospital in Zhejiang Province, Ximen Street, Linhai City, Zhejiang 317000, China
- Taizhou Integrated Traditional Chinese and Western Medicine Hospital in Zhejiang Province, Shangcheng Street, Zeguo Town, Wengling City, Zhejiang 317200, China
| | - Zhi Lin
- Taizhou Hospital in Zhejiang Province, Ximen Street, Linhai City, Zhejiang 317000, China
| | - Lizhi Wu
- Taizhou Hospital in Zhejiang Province, Ximen Street, Linhai City, Zhejiang 317000, China
| | - Youmao Zheng
- Taizhou Hospital in Zhejiang Province, Ximen Street, Linhai City, Zhejiang 317000, China
| | - Huifeng Xi
- Taizhou Hospital in Zhejiang Province, Ximen Street, Linhai City, Zhejiang 317000, China
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10
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Aghajani Mir M. Vault RNAs (vtRNAs): Rediscovered non-coding RNAs with diverse physiological and pathological activities. Genes Dis 2024; 11:772-787. [PMID: 37692527 PMCID: PMC10491885 DOI: 10.1016/j.gendis.2023.01.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 01/16/2023] [Indexed: 04/05/2023] Open
Abstract
The physicochemical characteristics of RNA admit non-coding RNAs to perform a different range of biological acts through various mechanisms and are involved in regulating a diversity of fundamental processes. Notably, some reports of pathological conditions have proved abnormal expression of many non-coding RNAs guides the ailment. Vault RNAs are a class of non-coding RNAs containing stem regions or loops with well-conserved sequence patterns that play a fundamental role in the function of vault particles through RNA-ligand, RNA-RNA, or RNA-protein interactions. Taken together, vault RNAs have been proposed to be involved in a variety of functions such as cell proliferation, nucleocytoplasmic transport, intracellular detoxification processes, multidrug resistance, apoptosis, and autophagy, and serve as microRNA precursors and signaling pathways. Despite decades of investigations devoted, the biological function of the vault particle or the vault RNAs is not yet completely cleared. In this review, the current scientific assertions of the vital vault RNAs functions were discussed.
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Affiliation(s)
- Mahsa Aghajani Mir
- Deputy of Research and Technology, Health Research Institute, Babol University of Medical Sciences, Babol 47176-4774, Iran
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11
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Aleksandrova KV, Vorobev ML, Suvorova II. mTOR pathway occupies a central role in the emergence of latent cancer cells. Cell Death Dis 2024; 15:176. [PMID: 38418814 PMCID: PMC10902345 DOI: 10.1038/s41419-024-06547-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/18/2024] [Accepted: 02/07/2024] [Indexed: 03/02/2024]
Abstract
The current focus in oncology research is the translational control of cancer cells as a major mechanism of cellular plasticity. Recent evidence has prompted a reevaluation of the role of the mTOR pathway in cancer development leading to new conclusions. The mechanistic mTOR inhibition is well known to be a tool for generating quiescent stem cells and cancer cells. In response to mTOR suppression, quiescent cancer cells dynamically change their proteome, triggering alternative non-canonical translation mechanisms. The shift to selective translation may have clinical relevance, since quiescent tumor cells can acquire new phenotypical features. This review provides new insights into the patterns of mTOR functioning in quiescent cancer cells, enhancing our current understanding of the biology of latent metastasis.
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Affiliation(s)
| | - Mikhail L Vorobev
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation
| | - Irina I Suvorova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russian Federation.
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12
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Delaunay S, Helm M, Frye M. RNA modifications in physiology and disease: towards clinical applications. Nat Rev Genet 2024; 25:104-122. [PMID: 37714958 DOI: 10.1038/s41576-023-00645-2] [Citation(s) in RCA: 106] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2023] [Indexed: 09/17/2023]
Abstract
The ability of chemical modifications of single nucleotides to alter the electrostatic charge, hydrophobic surface and base pairing of RNA molecules is exploited for the clinical use of stable artificial RNAs such as mRNA vaccines and synthetic small RNA molecules - to increase or decrease the expression of therapeutic proteins. Furthermore, naturally occurring biochemical modifications of nucleotides regulate RNA metabolism and function to modulate crucial cellular processes. Studies showing the mechanisms by which RNA modifications regulate basic cell functions in higher organisms have led to greater understanding of how aberrant RNA modification profiles can cause disease in humans. Together, these basic science discoveries have unravelled the molecular and cellular functions of RNA modifications, have provided new prospects for therapeutic manipulation and have led to a range of innovative clinical approaches.
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Affiliation(s)
- Sylvain Delaunay
- Deutsches Krebsforschungszentrum (DKFZ), Division of Mechanisms Regulating Gene Expression, Heidelberg, Germany
| | - Mark Helm
- Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Michaela Frye
- Deutsches Krebsforschungszentrum (DKFZ), Division of Mechanisms Regulating Gene Expression, Heidelberg, Germany.
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13
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Zhao Y, Xing C, Peng H. ALYREF (Aly/REF export factor): A potential biomarker for predicting cancer occurrence and therapeutic efficacy. Life Sci 2024; 338:122372. [PMID: 38135116 DOI: 10.1016/j.lfs.2023.122372] [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: 10/04/2023] [Revised: 12/09/2023] [Accepted: 12/18/2023] [Indexed: 12/24/2023]
Abstract
5-Methylcytosine (m5C) methylation is present in almost all types of RNA as an essential epigenetic modification. It is dynamically modulated by its associated enzymes, including m5C methyltransferases (NSUN, DNMT and TRDMT family members), demethylases (TET family and ALKBH1) and binding proteins (YTHDF2, ALYREF and YBX1). Among them, aberrant expression of the RNA-binding protein ALYREF can facilitate a variety of malignant phenotypes such as maintenance of proliferation, malignant heterogeneity, metastasis, and drug resistance to cell death through different regulatory mechanisms, including pre-mRNA processing, mRNA stability, and nuclear-cytoplasmic shuttling. The induction of these cellular processes by ALYREF results in treatment resistance and poor outcomes for patients. However, there are currently few reports of clinical applications or drug trials related to ALYREF. In addition, the looming observations on the role of ALYREF in the mechanisms of carcinogenesis and disease prognosis have triggered considerable interest, but critical evidence is not available. For example, animal experiments and ALYREF small molecule inhibitor trials. In this review, we, therefore, revisit the literature on ALYREF and highlight its importance as a prognostic biomarker for early prevention and as a therapeutic target.
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Affiliation(s)
- Yan Zhao
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Cheng Xing
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Hongling Peng
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Tumor Models and Individualized Medicine, Changsha, Hunan 410011, China; Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan 410011, China.
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14
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Wadhwa N, Kapoor S, Kapoor M. Arabidopsis T-DNA mutants affected in TRDMT1/DNMT2 show differential protein synthesis and compromised stress tolerance. FEBS J 2024; 291:92-113. [PMID: 37584564 DOI: 10.1111/febs.16935] [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: 01/21/2023] [Revised: 07/18/2023] [Accepted: 08/14/2023] [Indexed: 08/17/2023]
Abstract
TRDMT1/DNMT2 belongs to the conserved family of nucleic acid methyltransferases. Unlike the animal systems, studies on TRDMT1/DNMT2 in land plants have been limited. We show that TRDMT1/DNMT2 is strongly conserved in the green lineage. Studies in mosses have previously shown that TRDMT1/DNMT2 plays a crucial role in modulating molecular networks involved in stress perception and signalling and in transcription/stability of specific tRNAs under stress. To gain deeper insight into its biological roles in a flowering plant, we examined more closely the previously reported Arabidopsis SALK_136635C line deficient in TRDMT1/DNMT2 function [Goll MG et al. (2006) Science 311, 395-398]. RNAs derived from Arabidopsis Dnmt2-deficient plants lacked m5 C38 in tRNAAsp . In this study, by transient expression assays we show that Arabidopsis TRDMT1/DNMT2 is distributed in the nucleus, cytoplasm and RNA-processing bodies, suggesting a role for TRDMT1/DNMT2 in RNA metabolic processes possibly by shuttling between cellular compartments. Bright-field and high-resolution SEM and qPCR analysis reveal roles of TRDMT1/DNMT2 in proper growth and developmental progression. Quantitative proteome analysis by LC-MS/MS coupled with qPCR shows AtTRDMT1/AtDNMT2 function to be crucial for protein synthesis and cellular homeostasis via housekeeping roles and proteins with poly-Asp stretches and RNA pol II activity on selected genes are affected in attrdmt1/atdnmt2. This shift in metabolic pathways primes the mutant plants to become increasingly sensitive to oxidative and osmotic stress. Taken together, our study sheds light on the mechanistic role of TRDMT1/DNMT2 in a flowering plant.
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Affiliation(s)
- Nikita Wadhwa
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Sanjay Kapoor
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
- Interdisciplinary Centre for Plant Genomics and Department of Plant Molecular Biology, University of Delhi South Campus, New Delhi, India
| | - Meenu Kapoor
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
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15
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Abstract
ConspectusMore than 170 different types of chemical modifications have been identified on diverse types of RNA, collectively known as the epitranscriptome. Among them, N6-methyladenine (m6A), 5-methylcytosine (m5C), N1-methyladenine (m1A), and N7-methylguanosine (m7G) as the ubiquitous post-transcriptional modification are widely involved in regulating the metabolic processes such as RNA degradation, translation, stability, and export, mediating important physiological and pathological processes such as stress regulation, immune response, development, and tumorigenesis. Recently, the regulatory role of RNA modification during developmental processes is getting more attention. Therefore, the development of low-input even single-cell and high-resolution sequencing technologies is crucial for the exploration of the regulatory roles of RNA modifications in these important biological events of trace samples.This account focuses on the roles of RNA modifications in various developmental processes. We describe the distribution characteristics of various RNA modifications, catalytic enzymes, binding proteins, and the development of sequencing technologies. RNA modification is dynamically reversible, which can be catalyzed by methyltransferases and eliminated by demethylases. RNA m6A is the most abundant post-transcriptional modification on eukaryote mRNA, which is mainly concentrated near the stop codon, and involves in RNA metabolism regulation. RNA m5C, another most studied RNA modification, has been identified in a various of organisms and RNA species, mainly enriched in the regions downstream of translation initiation sites and broadly distributes across the whole coding sequence (CDS) in mammalian mRNAs. RNA m1A, with a lower abundance than m6A, is widely distributed in various RNA types, mainly locates in the 5' untranslated region (5'UTR) of mRNA and regulates translation. RNA m7G, one of the most common RNA modifications in eukaryotes, has been identified at cap regions and internal positions of RNAs and recently gained considerable attention.Thanks to the development of sequencing technology, m6A has been found to regulate the tumorigenic process, including tumor proliferation, invasion, and metastasis by modulating oncogenes and tumor suppressor genes, and affect oocyte maturation and embryonic development through regulating maternal and zygotic genes. m5C related proteins have been identified to participate in embryonic development, plant growth, and neural stem cell differentiation in a m5C dependent manner. m1A also has been revealed to be involved in these developmental processes. m7G dysregulation mainly involves in neurodevelopmental disorders and neurodegenerative diseases.Collectively, we summarized the gradually exhibited roles of RNA methylation during development, and discussed the possibility of RNA modifications as candidate biomarkers and potential therapeutic targets. The technological development is anticipated as the major driving force to expand our knowledge in this field.
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Affiliation(s)
- Meng-Ke Wang
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, P. R. China
| | - Chun-Chun Gao
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, P. R. China
| | - Yun-Gui Yang
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, P. R. China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, P. R. China
- Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
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16
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Imbriano C, Moresi V, Belluti S, Renzini A, Cavioli G, Maretti E, Molinari S. Epitranscriptomics as a New Layer of Regulation of Gene Expression in Skeletal Muscle: Known Functions and Future Perspectives. Int J Mol Sci 2023; 24:15161. [PMID: 37894843 PMCID: PMC10606696 DOI: 10.3390/ijms242015161] [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: 09/14/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Epitranscriptomics refers to post-transcriptional regulation of gene expression via RNA modifications and editing that affect RNA functions. Many kinds of modifications of mRNA have been described, among which are N6-methyladenosine (m6A), N1-methyladenosine (m1A), 7-methylguanosine (m7G), pseudouridine (Ψ), and 5-methylcytidine (m5C). They alter mRNA structure and consequently stability, localization and translation efficiency. Perturbation of the epitranscriptome is associated with human diseases, thus opening the opportunity for potential manipulations as a therapeutic approach. In this review, we aim to provide an overview of the functional roles of epitranscriptomic marks in the skeletal muscle system, in particular in embryonic myogenesis, muscle cell differentiation and muscle homeostasis processes. Further, we explored high-throughput epitranscriptome sequencing data to identify RNA chemical modifications in muscle-specific genes and we discuss the possible functional role and the potential therapeutic applications.
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Affiliation(s)
- Carol Imbriano
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (E.M.)
| | - Viviana Moresi
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC), University of Rome “La Sapienza”, 00181 Rome, Italy;
| | - Silvia Belluti
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (E.M.)
| | - Alessandra Renzini
- Unit of Histology and Medical Embryology, Department of Human Anatomy, Histology, Forensic Medicine and Orthopedics, University of Rome “La Sapienza”, 00161 Rome, Italy; (A.R.); (G.C.)
| | - Giorgia Cavioli
- Unit of Histology and Medical Embryology, Department of Human Anatomy, Histology, Forensic Medicine and Orthopedics, University of Rome “La Sapienza”, 00161 Rome, Italy; (A.R.); (G.C.)
| | - Eleonora Maretti
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (E.M.)
| | - Susanna Molinari
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (E.M.)
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17
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Kong Y, Yu J, Ge S, Fan X. Novel insight into RNA modifications in tumor immunity: Promising targets to prevent tumor immune escape. Innovation (N Y) 2023; 4:100452. [PMID: 37485079 PMCID: PMC10362524 DOI: 10.1016/j.xinn.2023.100452] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/23/2023] [Indexed: 07/25/2023] Open
Abstract
An immunosuppressive state is a typical feature of the tumor microenvironment. Despite the dramatic success of immune checkpoint inhibitor (ICI) therapy in preventing tumor cell escape from immune surveillance, primary and acquired resistance have limited its clinical use. Notably, recent clinical trials have shown that epigenetic drugs can significantly improve the outcome of ICI therapy in various cancers, indicating the importance of epigenetic modifications in immune regulation of tumors. Recently, RNA modifications (N6-methyladenosine [m6A], N1-methyladenosine [m1A], 5-methylcytosine [m5C], etc.), novel hotspot areas of epigenetic research, have been shown to play crucial roles in protumor and antitumor immunity. In this review, we provide a comprehensive understanding of how m6A, m1A, and m5C function in tumor immunity by directly regulating different immune cells as well as indirectly regulating tumor cells through different mechanisms, including modulating the expression of immune checkpoints, inducing metabolic reprogramming, and affecting the secretion of immune-related factors. Finally, we discuss the current status of strategies targeting RNA modifications to prevent tumor immune escape, highlighting their potential.
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Affiliation(s)
- Yuxin Kong
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
| | - Jie Yu
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
| | - Shengfang Ge
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200001, China
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18
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Abstract
The study of eukaryotic tRNA processing has given rise to an explosion of new information and insights in the last several years. We now have unprecedented knowledge of each step in the tRNA processing pathway, revealing unexpected twists in biochemical pathways, multiple new connections with regulatory pathways, and numerous biological effects of defects in processing steps that have profound consequences throughout eukaryotes, leading to growth phenotypes in the yeast Saccharomyces cerevisiae and to neurological and other disorders in humans. This review highlights seminal new results within the pathways that comprise the life of a tRNA, from its birth after transcription until its death by decay. We focus on new findings and revelations in each step of the pathway including the end-processing and splicing steps, many of the numerous modifications throughout the main body and anticodon loop of tRNA that are so crucial for tRNA function, the intricate tRNA trafficking pathways, and the quality control decay pathways, as well as the biogenesis and biology of tRNA-derived fragments. We also describe the many interactions of these pathways with signaling and other pathways in the cell.
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Affiliation(s)
- Eric M Phizicky
- Department of Biochemistry and Biophysics and Center for RNA Biology, University of Rochester School of Medicine, Rochester, New York 14642, USA
| | - Anita K Hopper
- Department of Molecular Genetics and Center for RNA Biology, Ohio State University, Columbus, Ohio 43235, USA
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19
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Muhammad N, Hussain SI, Rehman ZU, Khan SA, Jan S, Khan N, Muzammal M, Abbasi SW, Kakar N, Rehman ZU, Khan MA, Mirza MU, Muhammad N, Khan S, Wasif N. Autosomal recessive variants c.953A>C and c.97-1G>C in NSUN2 causing intellectual disability: a molecular dynamics simulation study of loss-of-function mechanisms. Front Neurol 2023; 14:1168307. [PMID: 37305761 PMCID: PMC10249782 DOI: 10.3389/fneur.2023.1168307] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/28/2023] [Indexed: 06/13/2023] Open
Abstract
Introduction Intellectual disability (ID) is a clinically and genetically heterogeneous disorder. It drastically affects the learning capabilities of patients and eventually reduces their IQ level below 70. Methods The current genetic study ascertained two consanguineous Pakistani families suffering from autosomal recessive intellectual developmental disorder-5 (MRT5). We have used exome sequencing followed by Sanger sequencing to identify the disease-causing variants. Results and discussion Genetic analysis using whole exome sequencing in these families identified two novel mutations in the NSUN2 (NM_017755.5). Family-A segregated a novel missense variant c.953A>C; p.Tyr318Ser in exon-9 of the NSUN2. The variant substituted an amino acid Tyr318, highly conserved among different animal species and located in the functional domain of NSUN2 known as "SAM-dependent methyltransferase RsmB/NOP2-type". Whereas in family B, we identified a novel splice site variant c.97-1G>C that affects the splice acceptor site of NSUN2. The identified splice variant (c.97-1G>C) was predicted to result in the skipping of exon-2, which would lead to a frameshift followed by a premature stop codon (p. His86Profs*16). Furthermore, it could result in the termination of translation and synthesis of dysfunctional protein, most likely leading to nonsense-mediated decay. The dynamic consequences of NSUN2 missense variant was further explored together with wildtype through molecular dynamic simulations, which uncovered the disruption of NSUN2 function due to a gain in structural flexibility. The present molecular genetic study further extends the mutational spectrum of NSUN2 to be involved in ID and its genetic heterogeneity in the Pakistani population.
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Affiliation(s)
- Nazif Muhammad
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Syeda Iqra Hussain
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Zia Ur Rehman
- Department of General Medicine, Northwest General Hospital & Research Center, Peshawar, Khyber Pakhtunkhwa, Pakistan
| | - Sher Alam Khan
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Samin Jan
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Niamatullah Khan
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Muzammal
- Gomal Center of Biochemistry and Biotechnology, Gomal University, D.I.Khan, Khyber Pakhtunkhwa, Pakistan
| | - Sumra Wajid Abbasi
- NUMS Department of Biological Sciences, National University of Medical Sciences, The Mall, Rawalpindi, Punjab, Pakistan
| | - Naseebullah Kakar
- Department of Biotechnology, Faculty of Life Sciences and Informatics, BUITEMS, Quetta, Pakistan
- Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
| | - Zia Ur Rehman
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Muzammil Ahmad Khan
- Gomal Center of Biochemistry and Biotechnology, Gomal University, D.I.Khan, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Usman Mirza
- Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada
| | - Noor Muhammad
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Saadullah Khan
- Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan
| | - Naveed Wasif
- Institute of Human Genetics, Ulm University, and Ulm University Medical Center, Ulm, Germany
- Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany
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20
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de Morree A, Rando TA. Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity. Nat Rev Mol Cell Biol 2023; 24:334-354. [PMID: 36922629 PMCID: PMC10725182 DOI: 10.1038/s41580-022-00568-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2022] [Indexed: 03/18/2023]
Abstract
Adult stem cells are important for mammalian tissues, where they act as a cell reserve that supports normal tissue turnover and can mount a regenerative response following acute injuries. Quiescent stem cells are well established in certain tissues, such as skeletal muscle, brain, and bone marrow. The quiescent state is actively controlled and is essential for long-term maintenance of stem cell pools. In this Review, we discuss the importance of maintaining a functional pool of quiescent adult stem cells, including haematopoietic stem cells, skeletal muscle stem cells, neural stem cells, hair follicle stem cells, and mesenchymal stem cells such as fibro-adipogenic progenitors, to ensure tissue maintenance and repair. We discuss the molecular mechanisms that regulate the entry into, maintenance of, and exit from the quiescent state in mice. Recent studies revealed that quiescent stem cells have a discordance between RNA and protein levels, indicating the importance of post-transcriptional mechanisms, such as alternative polyadenylation, alternative splicing, and translation repression, in the control of stem cell quiescence. Understanding how these mechanisms guide stem cell function during homeostasis and regeneration has important implications for regenerative medicine.
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Affiliation(s)
- Antoine de Morree
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
| | - Thomas A Rando
- Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, CA, USA.
- Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA.
- Center for Tissue Regeneration, Repair, and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
- Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA, USA.
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21
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Luo G, Xu W, Chen X, Xu W, Yang S, Wang J, Lin Y, Reinach PS, Yan D. The RNA m5C Methylase NSUN2 Modulates Corneal Epithelial Wound Healing. Invest Ophthalmol Vis Sci 2023; 64:5. [PMID: 36862118 PMCID: PMC9983701 DOI: 10.1167/iovs.64.3.5] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2023] Open
Abstract
Purpose The emerging epitranscriptomics offers insights into the physiopathological roles of various RNA modifications. The RNA methylase NOP2/Sun domain family member 2 (NSUN2) catalyzes 5-methylcytosine (m5C) modification of mRNAs. However, the role of NSUN2 in corneal epithelial wound healing (CEWH) remains unknown. Here we describe the functional mechanisms of NSUN2 in mediating CEWH. Methods RT-qPCR, Western blot, dot blot, and ELISA were used to determine the NSUN2 expression and overall RNA m5C level during CEWH. NSUN2 silencing or overexpression was performed to explore its involvement in CEWH both in vivo and in vitro. Multi-omics was integrated to reveal the downstream target of NSUN2. MeRIP-qPCR, RIP-qPCR, and luciferase assay, as well as in vivo and in vitro functional assays, clarified the molecular mechanism of NSUN2 in CEWH. Results The NSUN2 expression and RNA m5C level increased significantly during CEWH. NSUN2 knockdown significantly delayed CEWH in vivo and inhibited human corneal epithelial cells (HCEC) proliferation and migration in vitro, whereas NSUN2 overexpression prominently enhanced HCEC proliferation and migration. Mechanistically, we found that NSUN2 increased ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) translation through the binding of RNA m5C reader Aly/REF export factor. Accordingly, UHRF1 knockdown significantly delayed CEWH in vivo and inhibited HCEC proliferation and migration in vitro. Furthermore, UHRF1 overexpression effectively rescued the inhibitory effect of NSUN2 silencing on HCEC proliferation and migration. Conclusions NSUN2-mediated m5C modification of UHRF1 mRNA modulates CEWH. This finding highlights the critical importance of this novel epitranscriptomic mechanism in control of CEWH.
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Affiliation(s)
- Guangying Luo
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
| | - Weiwei Xu
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
| | - Xiaoyan Chen
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
| | - Wenji Xu
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
| | - Shuai Yang
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jiao Wang
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
| | - Yong Lin
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
| | - Peter S. Reinach
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
| | - Dongsheng Yan
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, China
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22
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Yang WL, Qiu W, Zhang T, Xu K, Gu ZJ, Zhou Y, Xu HJ, Yang ZZ, Shen B, Zhao YL, Zhou Q, Yang Y, Li W, Yang PY, Yang YG. Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis. Nat Commun 2023; 14:863. [PMID: 36792629 PMCID: PMC9932167 DOI: 10.1038/s41467-023-36595-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
T helper 17 (Th17) cells are a subset of CD4+ T helper cells involved in the inflammatory response in autoimmunity. Th17 cells secrete Th17 specific cytokines, such as IL-17A and IL17-F, which are governed by the master transcription factor RoRγt. However, the epigenetic mechanism regulating Th17 cell function is still not fully understood. Here, we reveal that deletion of RNA 5-methylcytosine (m5C) methyltransferase Nsun2 in mouse CD4+ T cells specifically inhibits Th17 cell differentiation and alleviates Th17 cell-induced colitis pathogenesis. Mechanistically, RoRγt can recruit Nsun2 to chromatin regions of their targets, including Il17a and Il17f, leading to the transcription-coupled m5C formation and consequently enhanced mRNA stability. Our study demonstrates a m5C mediated cell intrinsic function in Th17 cells and suggests Nsun2 as a potential therapeutic target for autoimmune disease.
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Affiliation(s)
- Wen-Lan Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Weinan Qiu
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.,Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ting Zhang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China
| | - Kai Xu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Zi-Juan Gu
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, 100101, China
| | - Yu Zhou
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Heng-Ji Xu
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhong-Zhou Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing University Medical School, 210093, Nanjing, China
| | - Bin Shen
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China
| | - Yong-Liang Zhao
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China
| | - Ying Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China. .,Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, 100101, China.
| | - Peng-Yuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Yun-Gui Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, China. .,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 101408, China. .,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China.
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23
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Fan Y, Lv X, Chen Z, Peng Y, Zhang M. m6A methylation: Critical roles in aging and neurological diseases. Front Mol Neurosci 2023; 16:1102147. [PMID: 36896007 PMCID: PMC9990872 DOI: 10.3389/fnmol.2023.1102147] [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: 11/29/2022] [Accepted: 02/02/2023] [Indexed: 02/23/2023] Open
Abstract
N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells, which participates in the functional regulation of various biological processes. It regulates the expression of targeted genes by affecting RNA translocation, alternative splicing, maturation, stability, and degradation. As recent evidence shows, of all organs, brain has the highest abundance of m6A methylation of RNAs, which indicates its regulating role in central nervous system (CNS) development and the remodeling of the cerebrovascular system. Recent studies have shown that altered m6A levels are crucial in the aging process and the onset and progression of age-related diseases. Considering that the incidence of cerebrovascular and degenerative neurologic diseases increase with aging, the importance of m6A in neurological manifestations cannot be ignored. In this manuscript, we focus on the role of m6A methylation in aging and neurological manifestations, hoping to provide a new direction for the molecular mechanism and novel therapeutic targets.
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Affiliation(s)
- Yishu Fan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xinyi Lv
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhuohui Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yanyi Peng
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengqi Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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24
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Kim YA, Siddiqui T, Blaze J, Cosacak MI, Winters T, Kumar A, Tein E, Sproul AA, Teich AF, Bartolini F, Akbarian S, Kizil C, Hargus G, Santa-Maria I. RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation. Acta Neuropathol 2023; 145:29-48. [PMID: 36357715 PMCID: PMC9807547 DOI: 10.1007/s00401-022-02511-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/12/2022]
Abstract
Epitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood. The identification of RNA-modifying enzymes has opened the possibility of investigating the role epitranscriptomic changes play in the disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one of the few known brain-enriched methyltransferases able to methylate mammalian non-coding RNAs. NSun2 loss of function due to autosomal-recessive mutations has been associated with neurological abnormalities in humans. Here, we show NSun2 is expressed in adult human neurons in the hippocampal formation and prefrontal cortex. Strikingly, we unravel decreased NSun2 protein expression and an increased ratio of pTau/NSun2 in the brains of patients with Alzheimer's disease (AD) as demonstrated by Western blotting and immunostaining, respectively. In a well-established Drosophila melanogaster model of tau-induced toxicity, reduction of NSun2 exacerbated tau toxicity, while overexpression of NSun2 partially abrogated the toxic effects. Conditional ablation of NSun2 in the mouse brain promoted a decrease in the miR-125b m6A levels and tau hyperphosphorylation. Utilizing human induced pluripotent stem cell (iPSC)-derived neuronal cultures, we confirmed NSun2 deficiency results in tau hyperphosphorylation. We also found that neuronal NSun2 levels decrease in response to amyloid-beta oligomers (AβO). Notably, AβO-induced tau phosphorylation and cell toxicity in human neurons could be rescued by overexpression of NSun2. Altogether, these results indicate that neuronal NSun2 deficiency promotes dysregulation of miR-125b and tau phosphorylation in AD and highlights a novel avenue for therapeutic targeting.
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Affiliation(s)
- Yoon A Kim
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA
- Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Tohid Siddiqui
- German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Dresden, Germany
| | - Jennifer Blaze
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Mehmet Ilyas Cosacak
- German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Dresden, Germany
| | - Tristan Winters
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA
- Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Atul Kumar
- Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Ellen Tein
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA
| | - Andrew A Sproul
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA
- Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Andrew F Teich
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA
- Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Francesca Bartolini
- Department of Pathology and Cell Biology, Columbia University, New York, USA
| | - Schahram Akbarian
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Caghan Kizil
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA
- German Center for Neurodegenerative Diseases (DZNE), Helmholtz Association, Dresden, Germany
- Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, USA
| | - Gunnar Hargus
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA.
- Department of Pathology and Cell Biology, Columbia University, New York, USA.
| | - Ismael Santa-Maria
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, USA.
- Department of Pathology and Cell Biology, Columbia University, New York, USA.
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Edificio E, Pozuelo de Alarcón, Madrid, 28223, Spain.
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25
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Zhang Y, Zhang LS, Dai Q, Chen P, Lu M, Kairis EL, Murugaiah V, Xu J, Shukla RK, Liang X, Zou Z, Cormet-Boyaka E, Qiu J, Peeples ME, Sharma A, He C, Li J. 5-methylcytosine (m 5C) RNA modification controls the innate immune response to virus infection by regulating type I interferons. Proc Natl Acad Sci U S A 2022; 119:e2123338119. [PMID: 36240321 PMCID: PMC9586267 DOI: 10.1073/pnas.2123338119] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
5-methylcytosine (m5C) is one of the most prevalent modifications of RNA, playing important roles in RNA metabolism, nuclear export, and translation. However, the potential role of RNA m5C methylation in innate immunity remains elusive. Here, we show that depletion of NSUN2, an m5C methyltransferase, significantly inhibits the replication and gene expression of a wide range of RNA and DNA viruses. Notably, we found that this antiviral effect is largely driven by an enhanced type I interferon (IFN) response. The antiviral signaling pathway is dependent on the cytosolic RNA sensor RIG-I but not MDA5. Transcriptome-wide mapping of m5C following NSUN2 depletion in human A549 cells revealed a marked reduction in the m5C methylation of several abundant noncoding RNAs (ncRNAs). However, m5C methylation of viral RNA was not noticeably altered by NSUN2 depletion. In NSUN2-depleted cells, the host RNA polymerase (Pol) III transcribed ncRNAs, in particular RPPH1 and 7SL RNAs, were substantially up-regulated, leading to an increase of unshielded 7SL RNA in cytoplasm, which served as a direct ligand for the RIG-I-mediated IFN response. In NSUN2-depleted cells, inhibition of Pol III transcription or silencing of RPPH1 and 7SL RNA dampened IFN signaling, partially rescuing viral replication and gene expression. Finally, depletion of NSUN2 in an ex vivo human lung model and a mouse model inhibits viral replication and reduces pathogenesis, which is accompanied by enhanced type I IFN responses. Collectively, our data demonstrate that RNA m5C methylation controls antiviral innate immunity through modulating the m5C methylome of ncRNAs and their expression.
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Affiliation(s)
- Yuexiu Zhang
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Li-Sheng Zhang
- Department of Chemistry, The University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
- The Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637
| | - Qing Dai
- Department of Chemistry, The University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
- The Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637
| | - Phylip Chen
- Center for Vaccines and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205
| | - Mijia Lu
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Elizabeth L. Kairis
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Valarmathy Murugaiah
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Jiayu Xu
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Rajni Kant Shukla
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Xueya Liang
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Zhongyu Zou
- Department of Chemistry, The University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
- The Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637
| | - Estelle Cormet-Boyaka
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
| | - Jianming Qiu
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS 66160
| | - Mark E. Peeples
- Center for Vaccines and Immunity, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43205
| | - Amit Sharma
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
- Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210
| | - Chuan He
- Department of Chemistry, The University of Chicago, Chicago, IL 60637
- Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637
- The Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637
- Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637
| | - Jianrong Li
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210
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26
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A Cross-Tissue Investigation of Molecular Targets and Physiological Functions of Nsun6 Using Knockout Mice. Int J Mol Sci 2022; 23:ijms23126584. [PMID: 35743028 PMCID: PMC9224068 DOI: 10.3390/ijms23126584] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/31/2022] [Accepted: 06/09/2022] [Indexed: 11/25/2022] Open
Abstract
The 5-methylcytosine (m5C) modification on an mRNA molecule is deposited by Nsun2 and its paralog Nsun6. While the physiological functions of Nsun2 have been carefully studied using gene knockout (KO) mice, the physiological functions of Nsun6 remain elusive. In this study, we generated an Nsun6-KO mouse strain, which exhibited no apparent phenotype in both the development and adult stages as compared to wild-type mice. Taking advantage of this mouse strain, we identified 80 high-confident Nsun6-dependent m5C sites by mRNA bisulfite sequencing in five different tissues and systematically analyzed the transcriptomic phenotypes of Nsun6-KO tissues by mRNA sequencing. Our data indicated that Nsun6 is not required for the homeostasis of these organs under laboratory housing conditions, but its loss may affect immune response in the spleen and oxidoreductive reaction in the liver under certain conditions. Additionally, we further investigated T-cell-dependent B cell activation in KO mice and found that Nsun6 is not essential for the germinal center B cell formation but is associated with the formation of antibody-secreting plasma cells. Finally, we found that Nsun6-mediated m5C modification does not have any evident influence on the stability of Nsun6 target mRNAs, suggesting that Nsun6-KO-induced phenotypes may be associated with other functions of the m5C modification or Nsun6 protein.
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27
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Role of main RNA modifications in cancer: N 6-methyladenosine, 5-methylcytosine, and pseudouridine. Signal Transduct Target Ther 2022; 7:142. [PMID: 35484099 PMCID: PMC9051163 DOI: 10.1038/s41392-022-01003-0] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 12/16/2022] Open
Abstract
Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N6-methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.
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28
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Song H, Zhang J, Liu B, Xu J, Cai B, Yang H, Straube J, Yu X, Ma T. Biological roles of RNA m 5C modification and its implications in Cancer immunotherapy. Biomark Res 2022; 10:15. [PMID: 35365216 PMCID: PMC8973801 DOI: 10.1186/s40364-022-00362-8] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/03/2022] [Indexed: 01/08/2023] Open
Abstract
Epigenetics including DNA and RNA modifications have always been the hotspot field of life sciences in the post-genome era. Since the first mapping of N6-methyladenosine (m6A) and the discovery of its widespread presence in mRNA, there are at least 160-170 RNA modifications have been discovered. These methylations occur in different RNA types, and their distribution is species-specific. 5-methylcytosine (m5C) has been found in mRNA, rRNA and tRNA of representative organisms from all kinds of species. As reversible epigenetic modifications, m5C modifications of RNA affect the fate of the modified RNA molecules and play important roles in various biological processes including RNA stability control, protein synthesis, and transcriptional regulation. Furthermore, accumulative evidence also implicates the role of RNA m5C in tumorigenesis. Here, we review the latest progresses in the biological roles of m5C modifications and how it is regulated by corresponding "writers", "readers" and "erasers" proteins, as well as the potential molecular mechanism in tumorigenesis and cancer immunotherapy.
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Affiliation(s)
- Hang Song
- Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, China
| | - Jianye Zhang
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Bin Liu
- Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China
| | - Jing Xu
- Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China
| | - Biao Cai
- Department of Biochemistry and Molecular Biology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, 230012, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, 230012, China
| | - Hai Yang
- Division of Surgical Research, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, 91054, Erlangen, Germany
| | - Julia Straube
- Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, 91054, Erlangen, Germany
| | - Xiyong Yu
- Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Teng Ma
- Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.
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Wilkinson E, Cui YH, He YY. Roles of RNA Modifications in Diverse Cellular Functions. Front Cell Dev Biol 2022; 10:828683. [PMID: 35350378 PMCID: PMC8957929 DOI: 10.3389/fcell.2022.828683] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/14/2022] [Indexed: 12/19/2022] Open
Abstract
Chemical modifications of RNA molecules regulate both RNA metabolism and fate. The deposition and function of these modifications are mediated by the actions of writer, reader, and eraser proteins. At the cellular level, RNA modifications regulate several cellular processes including cell death, proliferation, senescence, differentiation, migration, metabolism, autophagy, the DNA damage response, and liquid-liquid phase separation. Emerging evidence demonstrates that RNA modifications play active roles in the physiology and etiology of multiple diseases due to their pervasive roles in cellular functions. Here, we will summarize recent advances in the regulatory and functional role of RNA modifications in these cellular functions, emphasizing the context-specific roles of RNA modifications in mammalian systems. As m6A is the best studied RNA modification in biological processes, this review will summarize the emerging advances on the diverse roles of m6A in cellular functions. In addition, we will also provide an overview for the cellular functions of other RNA modifications, including m5C and m1A. Furthermore, we will also discuss the roles of RNA modifications within the context of disease etiologies and highlight recent advances in the development of therapeutics that target RNA modifications. Elucidating these context-specific functions will increase our understanding of how these modifications become dysregulated during disease pathogenesis and may provide new opportunities for improving disease prevention and therapy by targeting these pathways.
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Affiliation(s)
- Emma Wilkinson
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, United States
- Committee on Cancer Biology, University of Chicago, Chicago, IL, United States
| | - Yan-Hong Cui
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, United States
| | - Yu-Ying He
- Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, United States
- Committee on Cancer Biology, University of Chicago, Chicago, IL, United States
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30
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George H, Bashir ZI, Hussain S. Impaired hippocampal NMDAR-LTP in a transgenic model of NSUN2-deficiency. Neurobiol Dis 2022; 163:105597. [PMID: 34954053 DOI: 10.1016/j.nbd.2021.105597] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/09/2021] [Accepted: 12/19/2021] [Indexed: 11/28/2022] Open
Abstract
Biallelic loss-of-function NSUN2 mutations have recently been associated with cases of Autism Spectrum Condition (ASC), and NSun2-deficiency was also previously shown to cause a severe autosomal recessive intellectually disability disorder syndrome in which patients can sometimes display autistic behaviour. It has been demonstrated that NSUN2 can control protein synthesis rates via direct regulation of RNA methylation, and it is therefore of interest that other studies have suggested protein synthesis-dependent synaptic plasticity dysregulation as a mechanism for learning difficulties in various other autism-expressing conditions and disorders. Here we investigated NMDAR-LTP in a murine transgenic model harbouring loss-of-function mutation in the NSun2 gene and find an impairment of a protein synthesis-dependent form of this synaptic plasticity pathway. Our findings support the idea that NMDAR-LTP mis-regulation may represent a previously underappreciated mechanism associated with autism phenotypes.
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Affiliation(s)
- Harry George
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK; Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK
| | - Zafar I Bashir
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK.
| | - Shobbir Hussain
- Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
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31
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He X, Yang Z, Chu XY, Li YX, Zhu B, Huang YX, Wang W, Gao CY, Chen X, Zheng CY, Yang K, Zhang DL. ROR2 downregulation activates the MSX2/NSUN2/p21 regulatory axis and promotes dental pulp stem cell senescence. Stem Cells 2022; 40:290-302. [PMID: 35356984 DOI: 10.1093/stmcls/sxab024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 12/09/2021] [Indexed: 11/13/2022]
Abstract
Abstract
Cellular senescence severely limits the research and the application of dental pulp stem cells (DPSCs). A previous study conducted by our research group revealed a close implication of ROR2 in DPSC senescence, although the mechanism underlying the regulation of ROR2 in DPSCs remains poorly understood so far. In the present study, it was revealed that the expression of the ROR2-interacting transcription factor MSX2 was increased in aging DPSCs. It was demonstrated that the depletion of MSX2 inhibits the senescence of DPSCs and restores their self-renewal capacity, and the simultaneous overexpression of ROR2 enhanced this effect. Moreover, MSX2 knockdown suppressed the transcription of NSUN2, which regulates the expression of p21 by binding to and causing the m5C methylation of the 3'-UTR of p21 mRNA. Interestingly, ROR2 downregulation elevated the levels of MSX2 protein, and not the MSX2 mRNA expression, by reducing the phosphorylation level of MSX2 and inhibiting the RNF34-mediated MSX2 ubiquitination degradation. The results of the present study demonstrated the vital role of the ROR2/MSX2/NSUN2 axis in the regulation of DPSC senescence, thereby revealing a potential target for antagonizing DPSC aging.
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Affiliation(s)
- Xin He
- Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, China
| | - Zhan Yang
- Molecular Biology Laboratory, Talent and Academic Exchange Center, The Second Hospital of Hebei Medical University, Shijiazhang, China
| | - Xiao-yang Chu
- Department of Stomatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yun-xia Li
- Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Biao Zhu
- Department of Stomatology, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yan-xia Huang
- Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, China
| | - Wei Wang
- Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, China
| | - Chun-yan Gao
- Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, China
| | - Xu Chen
- Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, China
| | - Chun-yan Zheng
- Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, China
| | - Kai Yang
- Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Dong-liang Zhang
- Department of Orthodontics, Beijing Stomatological Hospital, Capital Medical University School of Stomatology, Capital Medical University, Beijing, China
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32
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Motorin Y, Helm M. RNA nucleotide methylation: 2021 update. WILEY INTERDISCIPLINARY REVIEWS. RNA 2022; 13:e1691. [PMID: 34913259 DOI: 10.1002/wrna.1691] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/22/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022]
Abstract
Among RNA modifications, transfer of methylgroups from the typical cofactor S-adenosyl-l-methionine by methyltransferases (MTases) to RNA is by far the most common reaction. Since our last review about a decade ago, the field has witnessed the re-emergence of mRNA methylation as an important mechanism in gene regulation. Attention has then spread to many other RNA species; all being included into the newly coined concept of the "epitranscriptome." The focus moved from prokaryotes and single cell eukaryotes as model organisms to higher eukaryotes, in particular to mammals. The perception of the field has dramatically changed over the past decade. A previous lack of phenotypes in knockouts in single cell organisms has been replaced by the apparition of MTases in numerous disease models and clinical investigations. Major driving forces of the field include methylation mapping techniques, as well as the characterization of the various MTases, termed "writers." The latter term has spilled over from DNA modification in the neighboring epigenetics field, along with the designations "readers," applied to mediators of biological effects upon specific binding to a methylated RNA. Furthermore "eraser" enzymes effect the newly discovered oxidative removal of methylgroups. A sense of reversibility and dynamics has replaced the older perception of RNA modification as a concrete-cast, irreversible part of RNA maturation. A related concept concerns incompletely methylated residues, which, through permutation of each site, lead to inhomogeneous populations of numerous modivariants. This review recapitulates the major developments of the past decade outlined above, and attempts a prediction of upcoming trends. This article is categorized under: RNA Processing > RNA Editing and Modification.
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Affiliation(s)
- Yuri Motorin
- Université de Lorraine, CNRS, INSERM, UMS2008/US40 IBSLor, EpiRNA-Seq Core Facility, Nancy, France.,Université de Lorraine, CNRS, UMR7365 IMoPA, Nancy, France
| | - Mark Helm
- Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-Universität, Mainz, Germany
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33
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Manduzio S, Kang H. RNA methylation in chloroplasts or mitochondria in plants. RNA Biol 2021; 18:2127-2135. [PMID: 33779501 PMCID: PMC8632092 DOI: 10.1080/15476286.2021.1909321] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/23/2021] [Indexed: 12/14/2022] Open
Abstract
Recent advances in our understanding of epitranscriptomic RNA methylation have expanded the complexity of gene expression regulation beyond epigenetic regulation involving DNA methylation and histone modifications. The instalment, removal, and interpretation of methylation marks on RNAs are carried out by writers (methyltransferases), erasers (demethylases), and readers (RNA-binding proteins), respectively. Contrary to an emerging body of evidence demonstrating the importance of RNA methylation in the diverse fates of RNA molecules, including splicing, export, translation, and decay in the nucleus and cytoplasm, their roles in plant organelles remain largely unclear and are only now being discovered. In particular, extremely high levels of methylation marks in chloroplast and mitochondrial RNAs suggest that RNA methylation plays essential roles in organellar biogenesis and functions in plants that are crucial for plant development and responses to environmental stimuli. Thus, unveiling the cellular components involved in RNA methylation in cell organelles is essential to better understand plant biology.
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Affiliation(s)
- Stefano Manduzio
- Department of Applied Biology, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, South Korea
| | - Hunseung Kang
- Department of Applied Biology, College of Agriculture and Life Sciences, Chonnam National University, Gwangju, South Korea
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34
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Li X, Peng J, Yi C. The epitranscriptome of small non-coding RNAs. Noncoding RNA Res 2021; 6:167-173. [PMID: 34820590 PMCID: PMC8581453 DOI: 10.1016/j.ncrna.2021.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/14/2021] [Accepted: 10/20/2021] [Indexed: 02/06/2023] Open
Abstract
Small non-coding RNAs are short RNA molecules and involved in many biological processes, including cell proliferation and differentiation, immune response, cell death, epigenetic regulation, metabolic control. A diversity of RNA modifications have been identified in these small non-coding RNAs, including transfer RNAs (tRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), small nuclear RNA (snRNA), small nucleolar RNAs (snoRNAs), and tRNA-derived small RNAs (tsRNAs). These post-transcriptional modifications are involved in the biogenesis and function of these small non-coding RNAs. In this review, we will summarize the existence of RNA modifications in the small non-coding RNAs and the emerging roles of these epitranscriptomic marks.
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Affiliation(s)
- Xiaoyu Li
- Department of Biochemistry and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.,State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Jinying Peng
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Chengqi Yi
- State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, 100871, China.,Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.,Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
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35
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Cayir A. RNA modifications as emerging therapeutic targets. WILEY INTERDISCIPLINARY REVIEWS. RNA 2021; 13:e1702. [PMID: 34816607 DOI: 10.1002/wrna.1702] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 12/11/2022]
Abstract
The field of epitranscriptome, posttranscriptional modifications to RNAs, is still growing up and has presented substantial evidences for the role of RNA modifications in diseases. In terms of new drug development, RNA modifications have a great promise for therapy. For example, more than 170 type of modifications exist in various types of RNAs. Regulatory genes and their roles in critical biological process have been identified and they are associated with several diseases. Current data, for example, identification of inhibitors targeting RNA modifications regulatory genes, strongly support the idea that RNA modifications have potential as emerging therapeutic targets. Therefore, in this review, RNA modifications and regulatory genes were comprehensively documented in terms of drug development by summarizing the findings from previous studies. It was discussed how RNA modifications or regulatory genes can be targeted by altering molecular mechanisms. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > RNA Editing and Modification.
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Affiliation(s)
- Akin Cayir
- Vocational Health College, Canakkale Onsekiz Mart University, Canakkale, Turkey.,Akershus Universitetssykehus, Medical Department, Lørenskog, Norway
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36
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Zhai CT, Tian YC, Tang ZX, Shao LJ. RNA methyltransferase NSUN2 promotes growth of hepatocellular carcinoma cells by regulating fizzy-related-1 in vitro and in vivo. Kaohsiung J Med Sci 2021; 37:991-999. [PMID: 34370374 DOI: 10.1002/kjm2.12430] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 06/16/2021] [Accepted: 06/20/2021] [Indexed: 12/29/2022] Open
Abstract
The aim of the study was to investigate the role of NSUN2 (NOP2/Sun RNA Methyltransferase Family Member 2) in hepatocellular carcinoma (HCC). The expressions of NSUN2 and FZR1 were measured. Cell viability, proliferation, and apoptosis were assessed. HCC xenograft in nude mouse model was established. Tumor weight and volume were examined. Tumor tissues were collected for immunohistochemistry (IHC). TCGA database analysis and clinical sample testing suggested that the transcript levels of NSUN2 and FZR1 were increased in HCC tissues. NSUN2 knockdown inhibited HCC cell viability and proliferation, and promoted cell apoptosis. Moreover, the effects of NSUN2 could be countered by overexpressing FZR1. In animal experiment, NSUN2 silencing suppressed tumor growth in nude mice by downregulating FZR1. In conclusion, NSUN2 has a regulatory effect on HCC cell proliferation and apoptosis. NSUN2 knockout could inhibit cellular processes in HCC and tumor growth, likely via FZR1 inhibition. This finding has not only revealed the role of NSUN2 in HCC growth, but also suggests a promising target for HCC treatment.
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Affiliation(s)
- Chun-Tao Zhai
- Department of General Surgery, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medcial University, Jiangsu Province, China
| | - Yi-Cheng Tian
- Department of General Surgery, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medcial University, Jiangsu Province, China
| | - Zu-Xiong Tang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Jiangsu Province, China
| | - Long-Jiang Shao
- Department of General Surgery, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medcial University, Jiangsu Province, China
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37
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RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis. Int J Mol Sci 2021; 22:ijms222111870. [PMID: 34769301 PMCID: PMC8584444 DOI: 10.3390/ijms222111870] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/16/2021] [Accepted: 10/26/2021] [Indexed: 02/06/2023] Open
Abstract
The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on the dynamic nature and spatiotemporal patterning of gene expression. These features of gene expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, and non-coding RNA activity, amongst others. In concert, another regulatory layer by which RNA bases and sugar residues are chemically modified enhances neuronal transcriptome complexity. Similar RNA modifications in other systems collectively constitute the cellular epitranscriptome that integrates and impacts various physiological processes. The epitranscriptome is dynamic and is reshaped constantly to regulate vital processes such as development, differentiation and stress responses. Perturbations of the epitranscriptome can lead to various pathogenic conditions, including cancer, cardiovascular abnormalities and neurological diseases. Recent advances in next-generation sequencing technologies have enabled us to identify and locate modified bases/sugars on different RNA species. These RNA modifications modulate the stability, transport and, most importantly, translation of RNA. In this review, we discuss the formation and functions of some frequently observed RNA modifications—including methylations of adenine and cytosine bases, and isomerization of uridine to pseudouridine—at various layers of RNA metabolism, together with their contributions to abnormal physiological conditions that can lead to various neurodevelopmental and neurological disorders.
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38
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Saba JA, Liakath-Ali K, Green R, Watt FM. Translational control of stem cell function. Nat Rev Mol Cell Biol 2021; 22:671-690. [PMID: 34272502 DOI: 10.1038/s41580-021-00386-2] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2021] [Indexed: 12/22/2022]
Abstract
Stem cells are characterized by their ability to self-renew and differentiate into many different cell types. Research has focused primarily on how these processes are regulated at a transcriptional level. However, recent studies have indicated that stem cell behaviour is strongly coupled to the regulation of protein synthesis by the ribosome. In this Review, we discuss how different translation mechanisms control the function of adult and embryonic stem cells. Stem cells are characterized by low global translation rates despite high levels of ribosome biogenesis. The maintenance of pluripotency, the commitment to a specific cell fate and the switch to cell differentiation depend on the tight regulation of protein synthesis and ribosome biogenesis. Translation regulatory mechanisms that impact on stem cell function include mTOR signalling, ribosome levels, and mRNA and tRNA features and amounts. Understanding these mechanisms important for stem cell self-renewal and differentiation may also guide our understanding of cancer grade and metastasis.
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Affiliation(s)
- James A Saba
- Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kifayathullah Liakath-Ali
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Rachel Green
- Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Fiona M Watt
- King's College London Centre for Stem Cells and Regenerative Medicine, Guy's Hospital, London, UK.
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39
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Predictive value of m5C regulatory gene expression in pancreatic adenocarcinoma. Sci Rep 2021; 11:17529. [PMID: 34471186 PMCID: PMC8410865 DOI: 10.1038/s41598-021-96470-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 08/10/2021] [Indexed: 11/08/2022] Open
Abstract
Pancreatic adenocarcinoma (PAAD) is the most malignant digestive tumor. The global incidence of pancreatic cancer has been rapidly trending upwards, necessitating an exploration of potential prognostic biomarkers and mechanisms of disease development. One of the most prevalent RNA modifications is 5-methylcytosine (m5C); however, its contribution to PAAD remains unclear. Data from The Cancer Genome Atlas (TCGA) database, including genes, copy number variations (CNVs), and simple nucleotide variations (SNVs), were obtained in the present study to identify gene signatures and prognostic values for m5C regulators in PAAD. Regulatory gene m5C changes were significantly correlated with TP53, BRCA1, CDKN2A, and ATM genes, which play important roles in PAAD pathogenesis. In particular, there was a significant relationship between m5C regulatory gene CNVs, especially in genes encoding epigenetic “writers”. According to m5C-regulated gene expression in clinically graded cases, one m5C-regulated genes, DNMT3A, showed both a strong effect on CNVs and a significant correlation between expression level and clinical grade (P < 0.05). Furthermore, low DNMT3A expression was not only associated with poor PAAD patient prognosis but also with the ribosomal processing. The relationship between low DNMT3A expression and poor prognosis was confirmed in an International Cancer Genome Consortium (ICGC) validation dataset.
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40
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Blaze J, Navickas A, Phillips HL, Heissel S, Plaza-Jennings A, Miglani S, Asgharian H, Foo M, Katanski CD, Watkins CP, Pennington ZT, Javidfar B, Espeso-Gil S, Rostandy B, Alwaseem H, Hahn CG, Molina H, Cai DJ, Pan T, Yao WD, Goodarzi H, Haghighi F, Akbarian S. Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior. Nat Commun 2021; 12:4913. [PMID: 34389722 PMCID: PMC8363735 DOI: 10.1038/s41467-021-24969-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 07/16/2021] [Indexed: 02/07/2023] Open
Abstract
Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.
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Affiliation(s)
- J Blaze
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - A Navickas
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - H L Phillips
- Departments of Psychiatry and Behavioral Sciences, Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA
| | - S Heissel
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - A Plaza-Jennings
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - S Miglani
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - H Asgharian
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - M Foo
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - C D Katanski
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - C P Watkins
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - Z T Pennington
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - B Javidfar
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - S Espeso-Gil
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - B Rostandy
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - H Alwaseem
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - C G Hahn
- Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA
| | - H Molina
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - D J Cai
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - T Pan
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - W D Yao
- Departments of Psychiatry and Behavioral Sciences, Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA
| | - H Goodarzi
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - F Haghighi
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Research and Development Service, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
| | - S Akbarian
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
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41
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Myllymäki H, Astorga Johansson J, Grados Porro E, Elliot A, Moses T, Feng Y. Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis. Front Cell Dev Biol 2021; 9:684036. [PMID: 34414180 PMCID: PMC8369915 DOI: 10.3389/fcell.2021.684036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/13/2021] [Indexed: 12/24/2022] Open
Abstract
Metabolic rewiring is a critical hallmark of tumorigenesis and is essential for the development of cancer. Although many key features of metabolic alteration that are crucial for tumor cell survival, proliferation and progression have been identified, these are obtained from studies with established tumors and cancer cell lines. However, information on the essential metabolic changes that occur during pre-neoplastic cell (PNC) development that enables its progression to full blown tumor is still lacking. Here, we present an untargeted metabolomics analysis of human oncogene HRASG12V induced PNC development, using a transgenic inducible zebrafish larval skin development model. By comparison with normal sibling controls, we identified six metabolic pathways that are significantly altered during PNC development in the skin. Amongst these altered pathways are pyrimidine, purine and amino acid metabolism that are common to the cancer metabolic changes that support rapid cell proliferation and growth. Our data also suggest alterations in post transcriptional modification of RNAs that might play a role in PNC development. Our study provides a proof of principle work flow for identifying metabolic alterations during PNC development driven by an oncogenic mutation. In the future, this approach could be combined with transcriptomic or proteomic approaches to establish the detailed interaction between signaling networks and cellular metabolic pathways that occur at the onset of tumor progression.
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Affiliation(s)
- Henna Myllymäki
- Centre for Inflammation Research, Queen’s Medical Research Institute, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, United Kingdom
| | - Jeanette Astorga Johansson
- Centre for Inflammation Research, Queen’s Medical Research Institute, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, United Kingdom
| | - Estefania Grados Porro
- Centre for Inflammation Research, Queen’s Medical Research Institute, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, United Kingdom
| | - Abigail Elliot
- Centre for Inflammation Research, Queen’s Medical Research Institute, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, United Kingdom
| | - Tessa Moses
- EdinOmics, SynthSys - Centre for Synthetic and Systems Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom
| | - Yi Feng
- Centre for Inflammation Research, Queen’s Medical Research Institute, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, United Kingdom
- Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
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42
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Gao Y, Fang J. RNA 5-methylcytosine modification and its emerging role as an epitranscriptomic mark. RNA Biol 2021; 18:117-127. [PMID: 34288807 DOI: 10.1080/15476286.2021.1950993] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
5-methylcytosine (m5C) is identified as an abundant and conserved modification in various RNAs, including tRNAs, mRNAs, rRNAs, and other non-coding RNAs. The application of high-throughput sequencing and mass spectrometry allowed for the detection of m5C at a single-nucleotide resolution and at a global abundance separately; this contributes to a better understanding of m5C modification and its biological functions. m5C modification plays critical roles in diverse aspects of RNA processing, including tRNA stability, rRNA assembly, and mRNA translation. Notably, altered m5C modifications and mutated RNA m5C methyltransferases are associated with diverse pathological processes, such as nervous system disorders and cancers. This review may provide new sights of molecular mechanism and functional importance of m5C modification.
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Affiliation(s)
- Yaqi Gao
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jingyuan Fang
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Abstract
Similar to epigenetic DNA and histone modifications, epitranscriptomic modifications (RNA modifications) have emerged as crucial regulators in temporal and spatial gene expression during eukaryotic development. To date, over 170 diverse types of chemical modifications have been identified upon RNA nucleobases. Some of these post-synthesized modifications can be reversibly installed, removed, and decoded by their specific cellular components and play critical roles in different biological processes. Accordingly, dysregulation of RNA modification effectors is tightly orchestrated with developmental processes. Here, we particularly focus on three well-studied RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N1-methyladenosine (m1A), and summarize recent knowledge of underlying mechanisms and critical roles of these RNA modifications in stem cell fate determination, embryonic development, and cancer progression, providing a better understanding of the whole association between epitranscriptomic regulation and mammalian development.
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Lv X, Liu X, Zhao M, Wu H, Zhang W, Lu Q, Chen X. RNA Methylation in Systemic Lupus Erythematosus. Front Cell Dev Biol 2021; 9:696559. [PMID: 34307373 PMCID: PMC8292951 DOI: 10.3389/fcell.2021.696559] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 05/28/2021] [Indexed: 12/18/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with complicated clinical manifestations. Although our understanding of the pathogenesis of SLE has greatly improved, the understanding of the pathogenic mechanisms of SLE is still limited by disease heterogeneity, and targeted therapy is still unavailable. Substantial evidence shows that RNA methylation plays a vital role in the mechanisms of the immune response, prompting speculation that it might also be related to the occurrence and development of SLE. RNA methylation has been a hot topic in the field of epigenetics in recent years. In addition to revealing the modification process, relevant studies have tried to explore the relationship between RNA methylation and the occurrence and development of various diseases. At present, some studies have provided evidence of a relationship between RNA methylation and SLE pathogenesis, but in-depth research and analysis are lacking. This review will start by describing the specific mechanism of RNA methylation and its relationship with the immune response to propose an association between RNA methylation and SLE pathogenesis based on existing studies and then discuss the future direction of this field.
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Affiliation(s)
- Xinyi Lv
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiaomin Liu
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Ming Zhao
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Haijing Wu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wuiguang Zhang
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
| | - Qianjin Lu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
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45
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Lü X, Fan Y, Kang S, Xiao B, Zhang M. RNA methylation and neurovascular unit remodeling. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2021; 46:536-544. [PMID: 34148891 PMCID: PMC10930208 DOI: 10.11817/j.issn.1672-7347.2021.200246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Indexed: 11/03/2022]
Abstract
RNA methylation is of great significance in the regulation of gene expression, among which the more important methylation modifiers are N6-methyladenosine (m6A) and 5-methylcytosine (m5C). The methylation process is mainly regulated by 3 kinds of proteins: methyltransferase, demethylase, and reader. m6A, m5C, and their related proteins have high abundance in the brain, and they have important roles in the development of the nervous system and the repair and remodeling of the vascular system. The neurovascular unit (NVU) is a unit of brain structure and function composed of neurons, capillaries, astrocytes, supporting cells, and extracellular matrix. The local microenvironment for NVU has an important role in nerve cell function repair, and the remodeling of NVU is of great significance in the prognosis of various neurological diseases.
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Affiliation(s)
- Xinyi Lü
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
| | - Yishu Fan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Shuntong Kang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Mengqi Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha 410008, China.
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46
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Allmeroth K, Kim CS, Annibal A, Pouikli A, Koester J, Derisbourg MJ, Andrés Chacón-Martínez C, Latza C, Antebi A, Tessarz P, Wickström SA, Denzel MS. N1-acetylspermidine is a determinant of hair follicle stem cell fate. J Cell Sci 2021; 134:261953. [PMID: 33973637 PMCID: PMC8182411 DOI: 10.1242/jcs.252767] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 03/20/2021] [Indexed: 12/17/2022] Open
Abstract
Stem cell differentiation is accompanied by increased mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine and spermine, which are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translational control remains obscure. Here, we investigate the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. Compared to progenitor cells, HFSCs showed lower translation rates, correlating with reduced polyamine levels. Surprisingly, overall polyamine depletion decreased translation but did not affect cell fate. In contrast, specific depletion of natural polyamines mediated by spermidine/spermine N1-acetyltransferase (SSAT; also known as SAT1) activation did not reduce translation but enhanced stemness. These results suggest a translation-independent role of polyamines in cell fate regulation. Indeed, we identified N1-acetylspermidine as a determinant of cell fate that acted through increasing self-renewal, and observed elevated N1-acetylspermidine levels upon depilation-mediated HFSC proliferation and differentiation in vivo. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions. This article has an associated First Person interview with the first author of the paper. Summary: Reduced protein synthesis is required for stem cell functions. Here, we delineate a complex interplay of polyamines and mRNA translation that determines hair follicle stem cell fate decisions.
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Affiliation(s)
- Kira Allmeroth
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
| | - Christine S Kim
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
| | - Andrea Annibal
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
| | - Andromachi Pouikli
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
| | - Janis Koester
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.,CECAD - Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
| | - Maxime J Derisbourg
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
| | | | - Christian Latza
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany
| | - Adam Antebi
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.,CECAD - Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
| | - Peter Tessarz
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.,CECAD - Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany
| | - Sara A Wickström
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.,CECAD - Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.,Helsinki Institute for Life Science, Biomedicum Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.,Wihuri Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland.,Stem Cells and Metabolism Research Program, Faculty of Medicine, Biomedicum Helsinki, Haartmaninkatu 8, FI-00290 Helsinki, Finland
| | - Martin S Denzel
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, D-50931 Cologne, Germany.,CECAD - Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Str. 26, D-50931 Cologne, Germany.,Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, D-50931 Cologne, Germany
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47
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Miao Y, Zhao Y, Han L, Ma X, Deng J, Yang J, Lü S, Shao F, Kong W, Wang W, Xu Q, Wang X, Feng J. NSun2 regulates aneurysm formation by promoting autotaxin expression and T cell recruitment. Cell Mol Life Sci 2021; 78:1709-1727. [PMID: 32734582 PMCID: PMC11073013 DOI: 10.1007/s00018-020-03607-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 07/09/2020] [Accepted: 07/22/2020] [Indexed: 01/08/2023]
Abstract
Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.
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Affiliation(s)
- Yutong Miao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Yang Zhao
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People's Republic of China
| | - Lulu Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Xiaolong Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Jiacheng Deng
- Cardiovascular Division, BHF Center for Vascular Regeneration, King's College London, London, UK
| | - Juan Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Silin Lü
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Fangyu Shao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Wei Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China
| | - Wengong Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Beijing, People's Republic of China
| | - Qingbo Xu
- Cardiovascular Division, BHF Center for Vascular Regeneration, King's College London, London, UK
| | - Xian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China.
| | - Juan Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, People's Republic of China.
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48
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Selmi T, Hussain S, Dietmann S, Heiß M, Borland K, Flad S, Carter JM, Dennison R, Huang YL, Kellner S, Bornelöv S, Frye M. Sequence- and structure-specific cytosine-5 mRNA methylation by NSUN6. Nucleic Acids Res 2021; 49:1006-1022. [PMID: 33330931 PMCID: PMC7826283 DOI: 10.1093/nar/gkaa1193] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022] Open
Abstract
The highly abundant N6-methyladenosine (m6A) RNA modification affects most aspects of mRNA function, yet the precise function of the rarer 5-methylcytidine (m5C) remains largely unknown. Here, we map m5C in the human transcriptome using methylation-dependent individual-nucleotide resolution cross-linking and immunoprecipitation (miCLIP) combined with RNA bisulfite sequencing. We identify NSUN6 as a methyltransferase with strong substrate specificity towards mRNA. NSUN6 primarily targeted three prime untranslated regions (3'UTR) at the consensus sequence motif CTCCA, located in loops of hairpin structures. Knockout and rescue experiments revealed enhanced mRNA and translation levels when NSUN6-targeted mRNAs were methylated. Ribosome profiling further demonstrated that NSUN6-specific methylation correlated with translation termination. While NSUN6 was dispensable for mouse embryonic development, it was down-regulated in human tumours and high expression of NSUN6 indicated better patient outcome of certain cancer types. In summary, our study identifies NSUN6 as a methyltransferase targeting mRNA, potentially as part of a quality control mechanism involved in translation termination fidelity.
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Affiliation(s)
- Tommaso Selmi
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
| | - Shobbir Hussain
- Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Sabine Dietmann
- Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, St. Louis, MO 63110, USA
| | - Matthias Heiß
- Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany
| | - Kayla Borland
- Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany
| | - Sophia Flad
- German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Jean-Michel Carter
- Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Rebecca Dennison
- Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0SR, UK
| | - Ya-Lin Huang
- Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
| | - Stefanie Kellner
- Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, Haus F, 81377 Munich, Germany
| | - Susanne Bornelöv
- Wellcome – MRC Cambridge Stem Cell Institute, University of Cambridge, Puddicombe Way, Cambridge CB2 0AW, UK
| | - Michaela Frye
- German Cancer Research Center – Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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49
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Nombela P, Miguel-López B, Blanco S. The role of m 6A, m 5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities. Mol Cancer 2021; 20:18. [PMID: 33461542 PMCID: PMC7812662 DOI: 10.1186/s12943-020-01263-w] [Citation(s) in RCA: 312] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 09/24/2020] [Indexed: 12/12/2022] Open
Abstract
RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.
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Affiliation(s)
- Paz Nombela
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007, Salamanca, Spain
| | - Borja Miguel-López
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007, Salamanca, Spain
| | - Sandra Blanco
- Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) - University of Salamanca, 37007, Salamanca, Spain. .,Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, 37007, Salamanca, Spain.
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50
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Chen YS, Yang WL, Zhao YL, Yang YG. Dynamic transcriptomic m 5 C and its regulatory role in RNA processing. WILEY INTERDISCIPLINARY REVIEWS-RNA 2021; 12:e1639. [PMID: 33438329 DOI: 10.1002/wrna.1639] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 11/30/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
RNA 5-methylcytosine (m5 C) is a prevalent RNA modification in multiple RNA species, including messenger RNAs (mRNAs), transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), and noncoding RNAs (ncRNAs), and broadly distributed from archaea, prokaryotes to eukaryotes. The multiple detecting techniques of m5 C have been developed, such as m5 C-RIP-seq, miCLIP-seq, AZA-IP-seq, RNA-BisSeq, TAWO-seq, and Nanopore sequencing. These high-throughput techniques, combined with corresponding analysis pipeline, provide a precise m5 C landscape contributing to the deciphering of its biological functions. The m5 C modification is distributed along with mRNA and enriched around 5'UTR and 3'UTR, and conserved in tRNAs and rRNAs. It is dynamically regulated by its related enzymes, including methyltransferases (NSUN, DNMT, and TRDMT family members), demethylases (TET families and ALKBH1), and binding proteins (ALYREF and YBX1). So far, accumulative studies have revealed that m5 C participates in a variety of RNA metabolism, including mRNA export, RNA stability, and translation. Depletion of m5 C modification in the organism could cause dysfunction of mitochondria, drawback of stress response, frustration of gametogenesis and embryogenesis, abnormality of neuro and brain development, and has been implicated in cell migration and tumorigenesis. In this review, we provide a comprehensive summary of dynamic regulatory elements of RNA m5 C, including methyltransferases (writers), demethylases (erasers), and binding proteins (readers). We also summarized the related detecting technologies and biological functions of the RNA 5-methylcytosine, and provided future perspectives in m5 C research. This article is categorized under: RNA Processing > RNA Editing and Modification.
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Affiliation(s)
- Yu-Sheng Chen
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center For Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Wen-Lan Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center For Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
| | - Yong-Liang Zhao
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center For Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Yun-Gui Yang
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.,China National Center For Bioinformation, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.,Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
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