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1
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Sarkar N, Kumar A. Paradigm shift: microRNAs interact with target gene promoters to cause transcriptional gene activation or silencing. Exp Cell Res 2025; 444:114372. [PMID: 39662662 DOI: 10.1016/j.yexcr.2024.114372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/29/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
MicroRNAs (miRNAs/miRs) are small (18-25 nucleotides in length), endogenous, non-coding RNAs that typically repress gene expression by interacting with the 3'untranslated regions (3'UTRs) of target mRNAs in the cytoplasm. While most of the scientific community still views miRNAs as repressors of gene expression, this review highlights their non-canonical novel role in the nucleus as activators or silencers of target gene transcription through miRNA-promoter interaction. The mechanistic details of the transcriptional role of miRNAs are yet to be elucidated, however, they can be explained by prospective models. In this review, we aim to discuss the different examples of transcriptional regulation by miRNAs and their possible mechanism of action, thereby offering a comprehensive perspective on the role of miRNAs in gene regulation and their importance in health and diseases.
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Affiliation(s)
- Neelanjana Sarkar
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, 560012, India.
| | - Arun Kumar
- Department of Developmental Biology and Genetics, Indian Institute of Science, Bangalore, 560012, India.
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2
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Shi Y, Huang R, Zhang Y, Feng Q, Pan X, Wang L. RNA Interference Induces BRCA1 Gene Methylation and Increases the Radiosensitivity of Breast Cancer Cells. Cancer Biother Radiopharm 2024; 39:406-424. [PMID: 35180362 DOI: 10.1089/cbr.2021.0346] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Purpose: To investigate the relationship between breast cancer susceptibility gene-1 (BRCA1) gene methylation and the radiosensitivity of breast cancer. Materials and Methods: The authors studied three breast cancer cell lines: MDA-MB-435, MDA-MB-231, and MCF-7 cells. They constructed five short hairpin RNAs (shRNAs) and five small interfering RNAs to target selected promoter loci and initiate sequence-specific methylation in breast cancer cells. Pyrosequencing was used to analyze the state of DNA methylation. Quantitative real-time polymerase chain reaction was used to detect BRCA1 mRNA expression and RNA-directed DNA methylation (RdDM)-related gene expression. Western blotting was performed to analyze BRCA1 protein expression. Colony formation assays and γ-histone H2A foci formation assays were conducted to assess the surviving fraction (SF) and double-strand break (DSB) repair ability of cells after irradiation. Results: The authors constructed five strains of lentivirus vectors and five plasmid vectors targeting BRCA1 promoter region. In MDA-MB-435 cells, lentivirus-mediated RNA interference targeting Site 1 of BRCA1 increased the methylation levels of BRCA1 and reduced BRCA1 mRNA and protein expression. The SF and the ability to repair DNA DSBs were reduced in the combined LV-BRCA1RNAi-Site 1 infection and irradiation group. Conclusions: The authors' findings suggest that the shRNA suppressed the expression levels of the BRCA1 gene and reduced the SF and DNA repair ability of cells after irradiation through RdDM. In summary, the radiosensitivity of breast cancer cells may correlate with BRCA1 methylation. Advances in Knowledge: The authors first utilized a lentivirus-based shRNA-mediated specific-sequence DNA methylation of the BRCA1 gene mediated by RdDM.
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Affiliation(s)
- Yuebin Shi
- Department of Pathology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Rui Huang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Qiang Feng
- Department of Pathology, 920th Hospital of Joint Logistics Support Force of PLA, Kunming, Yunnan, China
| | - Xinyan Pan
- Department of Pathology, 920th Hospital of Joint Logistics Support Force of PLA, Kunming, Yunnan, China
| | - Li Wang
- Department of Pathology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
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3
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Billi M, De Marinis E, Gentile M, Nervi C, Grignani F. Nuclear miRNAs: Gene Regulation Activities. Int J Mol Sci 2024; 25:6066. [PMID: 38892257 PMCID: PMC11172810 DOI: 10.3390/ijms25116066] [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: 04/22/2024] [Revised: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs which contribute to the regulation of many physiological and pathological processes. Conventionally, miRNAs perform their activity in the cytoplasm where they regulate gene expression by interacting in a sequence-specific manner with mature messenger RNAs. Recent studies point to the presence of mature miRNAs in the nucleus. This review summarizes current findings regarding the molecular activities of nuclear miRNAs. These molecules can regulate gene expression at the transcriptional level by directly binding DNA on the promoter or the enhancer of regulated genes. miRNAs recruit different protein complexes to these regions, resulting in activation or repression of transcription, through a number of molecular mechanisms. Hematopoiesis is presented as a paradigmatic biological process whereby nuclear miRNAs possess a relevant regulatory role. Nuclear miRNAs can influence gene expression by affecting nuclear mRNA processing and by regulating pri-miRNA maturation, thus impacting the biogenesis of miRNAs themselves. Overall, nuclear miRNAs are biologically active molecules that can be critical for the fine tuning of gene expression and deserve further studies in a number of physiological and pathological conditions.
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Affiliation(s)
- Monia Billi
- General Pathology and Department of Medicine, University of Perugia, 06132 Perugia, Italy;
| | - Elisabetta De Marinis
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, 04100 Latina, Italy; (E.D.M.); (M.G.); (C.N.)
| | - Martina Gentile
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, 04100 Latina, Italy; (E.D.M.); (M.G.); (C.N.)
| | - Clara Nervi
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome “La Sapienza”, 04100 Latina, Italy; (E.D.M.); (M.G.); (C.N.)
| | - Francesco Grignani
- General Pathology and Department of Medicine, University of Perugia, 06132 Perugia, Italy;
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4
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Yang S, Zou Q, Liang Y, Zhang D, Peng L, Li W, Li W, Liu M, Tong Y, Chen L, Xu P, Yang Z, Zhou K, Xiao J, Wang H, Yu W. miR-1246 promotes osteosarcoma cell migration via NamiRNA-enhancer network dependent on Argonaute 2. MedComm (Beijing) 2024; 5:e543. [PMID: 38585233 PMCID: PMC10999177 DOI: 10.1002/mco2.543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 04/09/2024] Open
Abstract
High metastatic propensity of osteosarcoma leads to its therapeutic failure and poor prognosis. Although nuclear activation miRNAs (NamiRNAs) are reported to activate gene transcription via targeting enhancer and further promote tumor metastasis, it remains uncertain whether NamiRNAs regulate osteosarcoma metastasis and their exact mechanism. Here, we found that extracellular vesicles of the malignant osteosarcoma cells (143B) remarkably increased the migratory abilities of MNNG cells representing the benign osteosarcoma cells by two folds, which attributed to their high miR-1246 levels. Specially, miR-1246 located in nucleus could activate the migration gene expression (such as MMP1) to accelerate MNNG cell migration through elevating the enhancer activities via increasing H3K27ac enrichment. Instead, MMP1 expression was dramatically inhibited after Argonaute 2 (AGO2) knockdown. Notably, in vitro assays demonstrated that AGO2 recognized the hybrids of miR-1246 and its enhancer DNA via PAZ domains to prevent their degradation from RNase H and these protective roles of AGO2 may favor the gene activation by miR-1246 in vivo. Collectively, our findings suggest that miR-1246 could facilitate osteosarcoma metastasis through interacting with enhancer to activate gene expression dependent on AGO2, highlighting the nuclear AGO2 as a guardian for NamiRNA-targeted gene activation and the potential of miR-1246 for osteosarcoma metastasis therapy.
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Affiliation(s)
- Shuai Yang
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Qingping Zou
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Ying Liang
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Dapeng Zhang
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Centre for Eco‐Environmental SciencesChinese Academy of SciencesBeijingChina
| | - Lina Peng
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Wei Li
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Wenxuan Li
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Mengxing Liu
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Ying Tong
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Lu Chen
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Peng Xu
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Zhicong Yang
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Kaicheng Zhou
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Jianru Xiao
- Department of Orthopaedic OncologyChangzheng HospitalNaval Medical UniversityShanghaiChina
| | - Hailin Wang
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Centre for Eco‐Environmental SciencesChinese Academy of SciencesBeijingChina
| | - Wenqiang Yu
- Shanghai Public Health Clinical Centre and Department of General SurgeryHuashan HospitalCancer Metastasis Institute and Laboratory of RNA EpigeneticsInstitutes of Biomedical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
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5
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Gu J, Li Y, Tian Y, Zhang Y, Cheng Y, Tang Y. Noncanonical functions of microRNAs in the nucleus. Acta Biochim Biophys Sin (Shanghai) 2024; 56:151-161. [PMID: 38167929 PMCID: PMC10984876 DOI: 10.3724/abbs.2023268] [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: 09/02/2023] [Accepted: 11/03/2023] [Indexed: 01/05/2024] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) that play their roles in the regulation of physiological and pathological processes. Originally, it was assumed that miRNAs only modulate gene expression posttranscriptionally in the cytoplasm by inducing target mRNA degradation. However, with further research, evidence shows that mature miRNAs also exist in the cell nucleus, where they can impact gene transcription and ncRNA maturation in several ways. This review provides an overview of novel models of nuclear miRNA functions. Some of the models remain to be verified by experimental evidence, and more details of the miRNA regulation network remain to be discovered in the future.
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Affiliation(s)
- Jiayi Gu
- College of Basic Medical SciencesShanghai Jiao Tong University School of MedicineShanghai200001China
| | - Yuanan Li
- College of Basic Medical SciencesShanghai Jiao Tong University School of MedicineShanghai200001China
| | - Youtong Tian
- College of Basic Medical SciencesShanghai Jiao Tong University School of MedicineShanghai200001China
| | - Yehao Zhang
- College of Basic Medical SciencesShanghai Jiao Tong University School of MedicineShanghai200001China
| | - Yongjun Cheng
- Department of Rheumatologythe First People’s Hospital of WenlingWenling317500China
| | - Yuanjia Tang
- Shanghai Institute of Rheumatology/Department of RheumatologyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai200001China
- State Key Laboratory of Oncogenes and Related GenesShanghai Cancer InstituteRenji HospitalShanghai200031China
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6
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He D, Mount SM, Patro R. scCensus: Off-target scRNA-seq reads reveal meaningful biology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.29.577807. [PMID: 38352549 PMCID: PMC10862729 DOI: 10.1101/2024.01.29.577807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/23/2024]
Abstract
Single-cell RNA-sequencing (scRNA-seq) provides unprecedented insights into cellular heterogeneity. Although scRNA-seq reads from most prevalent and popular tagged-end protocols are expected to arise from the 3' end of polyadenylated RNAs, recent studies have shown that "off-target" reads can constitute a substantial portion of the read population. In this work, we introduced scCensus, a comprehensive analysis workflow for systematically evaluating and categorizing off-target reads in scRNA-seq. We applied scCensus to seven scRNA-seq datasets. Our analysis of intergenic reads shows that these off-target reads contain information about chromatin structure and can be used to identify similar cells across modalities. Our analysis of antisense reads suggests that these reads can be used to improve gene detection and capture interesting transcriptional activities like antisense transcription. Furthermore, using splice-aware quantification, we find that spliced and unspliced reads provide distinct information about cell clusters and biomarkers, suggesting the utility of integrating signals from reads with different splicing statuses. Overall, our results suggest that off-target scRNA-seq reads contain underappreciated information about various transcriptional activities. These observations about yet-unexploited information in existing scRNA-seq data will help guide and motivate the community to improve current algorithms and analysis methods, and to develop novel approaches that utilize off-target reads to extend the reach and accuracy of single-cell data analysis pipelines.
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Affiliation(s)
- Dongze He
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA
- Program in Computational Biology, Bioinformatics and Genomices, University of Maryland, College Park, MD 20742, USA
| | - Stephen M. Mount
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Rob Patro
- Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD 20742, USA
- Department of Computer Science, University of Maryland, College Park, MD 20742, USA
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7
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Ramanathan K, Fekadie M, Padmanabhan G, Gulilat H. Long noncoding RNA: An emerging diagnostic and therapeutic target in kidney diseases. Cell Biochem Funct 2024; 42:e3901. [PMID: 38100151 DOI: 10.1002/cbf.3901] [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: 09/01/2023] [Revised: 11/13/2023] [Accepted: 11/29/2023] [Indexed: 01/26/2024]
Abstract
Long noncoding RNAs (lncRNAs) have critical roles in the development of many diseases including kidney disease. An increasing number of studies have shown that lncRNAs are involved in kidney development and that their dysregulation can result in distinct disease processes, including acute kidney injury, chronic kidney disease, and renal cell carcinoma. Understanding the roles of lncRNAs in kidney disease may provide new diagnostic and therapeutic opportunities in the clinic. This review provides an overview of lncRNA characteristics, and biological function and discusses specific studies that provide insight into the function and potential application of lncRNAs in kidney disease treatment.
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Affiliation(s)
- Kumaresan Ramanathan
- Department of Biomedical Sciences, Faculty of Medical Sciences, Institute of Health, Jimma University, Jimma, Ethiopia
| | - Minale Fekadie
- Department of Biomedical Sciences, Faculty of Medical Sciences, Institute of Health, Jimma University, Jimma, Ethiopia
| | | | - Henok Gulilat
- Department of Biomedical Sciences, Faculty of Medical Sciences, Institute of Health, Jimma University, Jimma, Ethiopia
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8
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Komlosh PG, Chen JL, Childs-Disney J, Disney MD, Canaani D. Broad-spectrum metastasis suppressing compounds and therapeutic uses thereof in human tumors. Sci Rep 2023; 13:20420. [PMID: 37990044 PMCID: PMC10663508 DOI: 10.1038/s41598-023-47478-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 11/14/2023] [Indexed: 11/23/2023] Open
Abstract
Previously, we have identified a novel human metastasis-inducing lncRNA (named SKAI1BC), that suppresses the KAI1/CD82 metastasis-suppressing gene and is upregulated in triple negative breast cancer and melanoma derived cell lines. Modeling of the SKAI1BC lncRNA secondary structure and its potential interaction with Inforna compounds, led us to identify several compounds that might bind the SKAI1BC lncRNA. We found that these compounds inhibit metastasis invasion and cell migration in culture, in all eight types of solid human cancers tested: several of which are the most lethal and/or frequent human malignancies. Moreover, in most cases, the mechanism of action of several of our compounds involves enhancement of KAI1/CD82 RNA level depending on the specific compound and the human tumor type. With the epigenetic inactivation of KAI1/CD82 in at least ten additional solid human cancers, this implies a very good chance to broaden the spectrum of human cancers affected by our compounds. This is the first time that modeling of a large lncRNA (> 700 bp) secondary structure followed by its potential interaction with Inforna like compounds database has led to the identification of potential biologically active small molecule drugs.
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Affiliation(s)
- Pnina Gottfried Komlosh
- Department of Biochemistry and Molecular Biology, George Wise Faculty of Life Sciences, Tel Aviv University, 69978, Ramat Aviv, Israel
| | - Jonathan L Chen
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Ave., Box 712, Rochester, NY, 14642, USA
| | - Jessica Childs-Disney
- Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, FL, 33458, USA
| | - Matthew D Disney
- Department of Chemistry, The Scripps Research Institute & UF Scripps Biomedical Research, 130 Scripps Way, Jupiter, FL, 33458, USA
| | - Dan Canaani
- Department of Biochemistry and Molecular Biology, George Wise Faculty of Life Sciences, Tel Aviv University, 69978, Ramat Aviv, Israel.
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9
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Dahiya N, Kaur M, Singh V. Potential roles of circulatory microRNAs in the onset and progression of renal and cardiac diseases: a focussed review for clinicians. Acta Cardiol 2023; 78:863-877. [PMID: 37318070 DOI: 10.1080/00015385.2023.2221150] [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: 10/29/2022] [Revised: 05/14/2023] [Accepted: 05/30/2023] [Indexed: 06/16/2023]
Abstract
The signalling mechanisms involving the kidney and heart are a niche of networks causing pathological conditions inducing inflammation, reactive oxidative species, cell apoptosis, and organ dysfunction during the onset of clinical complications. The clinical manifestation of the kidney and heart depends on various biochemical processes that influence organ dysfunction coexistence through circulatory networks, which hold utmost importance. The cells of both organs also influence remote communication, and evidence states that it may be explicitly by circulatory small noncoding RNAs, i.e. microRNAs (miRNAs). Recent developments target miRNAs as marker panels for disease diagnosis and prognosis. Circulatory miRNAs expressed in renal and cardiac disease can reveal relevant information about the niche of networks and gene transcription and regulated networks. In this review, we discuss the pertinent roles of identified circulatory miRNAs regulating signal transduction pathways critical in the onset of renal and cardiac disease, which can hold promising future targets for clinical diagnostic and prognostic purposes.
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Affiliation(s)
- Neha Dahiya
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Punjab, India
| | - Manpreet Kaur
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Punjab, India
| | - Varsha Singh
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Punjab, India
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10
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Narwidina A, Miyazaki A, Iwata K, Kurogoushi R, Sugimoto A, Kudo Y, Kawarabayashi K, Yamakawa Y, Akazawa Y, Kitamura T, Nakagawa H, Yamaguchi-Ueda K, Hasegawa T, Yoshizaki K, Fukumoto S, Yamamoto A, Ishimaru N, Iwasaki T, Iwamoto T. Iroquois homeobox 3 regulates odontoblast proliferation and differentiation mediated by Wnt5a expression. Biochem Biophys Res Commun 2023; 650:47-54. [PMID: 36773339 DOI: 10.1016/j.bbrc.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/02/2023] [Indexed: 02/09/2023]
Abstract
Iroquois homeobox (Irx) genes are TALE-class homeobox genes that are evolutionarily conserved across species and have multiple critical cellular functions in fundamental tissue development processes. Previous studies have shown that Irxs genes are expressed during tooth development. However, the precise roles of genes in teeth remain unclear. Here, we demonstrated for the first time that Irx3 is an essential molecule for the proliferation and differentiation of odontoblasts. Using cDNA synthesized from postnatal day 1 (P1) tooth germs, we examined the expression of all Irx genes (Irx1-Irx6) by RT-PCR and found that all genes except Irx4 were expressed in the tooth tissue. Irx1-Irx3 a were expressed in the dental epithelial cell line M3H1 cells, while Irx3 and Irx5 were expressed in the dental mesenchymal cell line mDP cells. Only Irx3 was expressed in both undifferentiated cell lines. Immunostaining also revealed the presence of IRX3 in the dental epithelial cells and mesenchymal condensation. Inhibition of endogenous Irx3 by siRNA blocks the proliferation and differentiation of mDP cells. Wnt3a, Wnt5a, and Bmp4 are factors involved in odontoblast differentiation and were highly expressed in mDP cells by quantitative PCR analysis. Interestingly, the expression of Wnt5a (but not Wnt3a or Bmp4) was suppressed by Irx3 siRNA. These results suggest that Irx3 plays an essential role in part through the regulation of Wnt5a expression during odontoblast proliferation and differentiation.
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Affiliation(s)
- Anrizandy Narwidina
- Department of Pediatric Dentistry, Graduate School of Oral Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan; Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Aya Miyazaki
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Kokoro Iwata
- Department of Pediatric Dentistry / Special Needs Dentistry, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan
| | - Rika Kurogoushi
- Department of Pediatric Dentistry / Special Needs Dentistry, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan
| | - Asuna Sugimoto
- Department of Pediatric Dentistry / Special Needs Dentistry, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan
| | - Yasusei Kudo
- Department of Oral Bioscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Keita Kawarabayashi
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Yoshihito Yamakawa
- Department of Pediatric Dentistry, Graduate School of Oral Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan; Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Yuki Akazawa
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Takamasa Kitamura
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Hiroshi Nakagawa
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Kimiko Yamaguchi-Ueda
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Tomokazu Hasegawa
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Keigo Yoshizaki
- Orthodontics and Dentofacial Orthopedics Section, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, 812-8582, Japan
| | - Satoshi Fukumoto
- Pediatric Dentistry Section, Division of Oral Health, Growth and Development, Kyushu University Faculty of Dental Science, Fukuoka, 812-8582, Japan
| | - Akihito Yamamoto
- Department of Tissue Regeneration, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Naozumi Ishimaru
- Department of Oral Molecular Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Tomonori Iwasaki
- Department of Pediatric Dentistry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8504, Japan
| | - Tsutomu Iwamoto
- Department of Pediatric Dentistry / Special Needs Dentistry, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8549, Japan.
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11
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Navigating the Multiverse of Antisense RNAs: The Transcription- and RNA-Dependent Dimension. Noncoding RNA 2022; 8:ncrna8060074. [PMID: 36412909 PMCID: PMC9680235 DOI: 10.3390/ncrna8060074] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 12/14/2022] Open
Abstract
Evidence accumulated over the past decades shows that the number of identified antisense transcripts is continuously increasing, promoting them from transcriptional noise to real genes with specific functions. Indeed, recent studies have begun to unravel the complexity of the antisense RNA (asRNA) world, starting from the multidimensional mechanisms that they can exert in physiological and pathological conditions. In this review, we discuss the multiverse of the molecular functions of asRNAs, describing their action through transcription-dependent and RNA-dependent mechanisms. Then, we report the workflow and methodologies to study and functionally characterize single asRNA candidates.
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12
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Cheng H, Zhang ES, Shi X, Cao PP, Pan BJ, Si XX, Liu Y, Yang N, Chu Y, Wang XC, Han X, Zhang ZH, Sun YJ. A Novel ATM Antisense Transcript ATM-AS Positively Regulates ATM Expression in Normal and Breast Cancer Cells. Curr Med Sci 2022; 42:681-691. [DOI: 10.1007/s11596-022-2585-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 02/02/2022] [Indexed: 11/03/2022]
Abstract
Abstract
Objective
The ataxia telangiectasia mutated (ATM) gene is a master regulator in cellular DNA damage response. The dysregulation of ATM expression is frequent in breast cancer, and is known to be involved in the carcinogenesis and prognosis of cancer. However, the underlying mechanism remains unclear. The bioinformatic analysis predicted a potential antisense transcript ATM-antisense (AS) from the opposite strand of the ATM gene. The purpose of this study was to identify ATM-AS and investigate the possible effect of ATM-AS on the ATM gene regulation.
Methods
Single strand-specific RT-PCR was performed to verify the predicted antisense transcript ATM-AS within the ATM gene locus. qRT-PCR and Western blotting were used to detect the expression levels of ATM-AS and ATM in normal and breast cancer cell lines as well as in tissue samples. Luciferase reporter gene assays, biological mass spectrometry, ChIP-qPCR and RIP were used to explore the function of ATM-AS in regulating the ATM expression. Immunofluorescence and host-cell reactivation (HCR) assay were performed to evaluate the biological significance of ATM-AS in ATM-mediated DNA damage repair. Breast cancer tissue samples were used for evaluating the correlation of the ATM-AS level with the ATM expression as well as prognosis of the patients.
Results
The ATM-AS significantly upregulated the ATM gene activity by recruiting KAT5 histone acetyltransferase to the gene promoter. The reduced ATM-AS level led to the abnormal downregulation of ATM expression, and impaired the ATM-mediated DNA damage repair in normal breast cells in vitro. The ATM-AS level was positively correlated with the ATM expression in the examined breast cancer tissue samples, and the patient prognosis.
Conclusion
The present study demonstrated that ATM-AS, an antisense transcript located within the ATM gene body, is an essential positive regulator of ATM expression, and functions by mediating the binding of KAT5 to the ATM promoter. These findings uncover the novel mechanism underlying the dysregulation of the ATM gene in breast cancer, and enrich our understanding of how an antisense transcript regulates its host gene.
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13
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Rojas-Pirela M, Andrade-Alviárez D, Medina L, Castillo C, Liempi A, Guerrero-Muñoz J, Ortega Y, Maya JD, Rojas V, Quiñones W, Michels PA, Kemmerling U. MicroRNAs: master regulators in host-parasitic protist interactions. Open Biol 2022; 12:210395. [PMID: 35702995 PMCID: PMC9198802 DOI: 10.1098/rsob.210395] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs present in a wide diversity of organisms. MiRNAs regulate gene expression at a post-transcriptional level through their interaction with the 3' untranslated regions of target mRNAs, inducing translational inhibition or mRNA destabilization and degradation. Thus, miRNAs regulate key biological processes, such as cell death, signal transduction, development, cellular proliferation and differentiation. The dysregulation of miRNAs biogenesis and function is related to the pathogenesis of diseases, including parasite infection. Moreover, during host-parasite interactions, parasites and host miRNAs determine the probability of infection and progression of the disease. The present review is focused on the possible role of miRNAs in the pathogenesis of diseases of clinical interest caused by parasitic protists. In addition, the potential role of miRNAs as targets for the design of drugs and diagnostic and prognostic markers of parasitic diseases is also discussed.
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Affiliation(s)
- Maura Rojas-Pirela
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile,Facultad de Farmacia y Bioanálisis, Universidad de Los Andes, Mérida, Venezuela
| | - Diego Andrade-Alviárez
- Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela
| | - Lisvaneth Medina
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Christian Castillo
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Núcleo de Investigación Aplicada en Ciencias Veterinarias y Agronómicas, Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Chile
| | - Ana Liempi
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Jesús Guerrero-Muñoz
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Yessica Ortega
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile,Facultad de Farmacia y Bioanálisis, Universidad de Los Andes, Mérida, Venezuela
| | - Juan Diego Maya
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
| | - Verónica Rojas
- Instituto de Biología, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile
| | - Wilfredo Quiñones
- Laboratorio de Enzimología de Parásitos, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela
| | - Paul A. Michels
- Centre for Immunity, Infection and Evolution and Centre for Translational and Chemical Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3FL, UK
| | - Ulrike Kemmerling
- Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile 8380453, Chile
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14
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Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex. Cell Rep 2022; 39:110673. [PMID: 35417682 DOI: 10.1016/j.celrep.2022.110673] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/26/2021] [Accepted: 03/22/2022] [Indexed: 11/22/2022] Open
Abstract
RNA activation (RNAa) is an uncharacterized mechanism of transcriptional activation mediated by small RNAs, such as microRNAs (miRNAs). A critical issue in RNAa research is that it is difficult to distinguish between changes in gene expression caused indirectly by post-transcriptional regulation and direct induction of gene expression by RNAa. Therefore, in this study, we seek to identify a key factor involved in RNAa, using the induction of ZMYND10 by miR-34a as a system to evaluate RNAa. We identify the positive transcription elongation factors CDK9 and DDX21, which form a complex with nuclear AGO and TNRC6A, as important transcriptional activators of RNAa. In addition, we find that inhibition of DDX21 suppresses RNAa by miR-34a and other miRNAs without inhibiting post-transcriptional regulation. Our findings reveal a strong connection between RNAa and release of paused Pol II, facilitating RNAa research by making it possible to separately analyze post-transcriptional regulation and RNAa.
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15
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Laitinen P, Väänänen MA, Kolari IL, Mäkinen PI, Kaikkonen MU, Weinberg MS, Morris KV, Korhonen P, Malm T, Ylä-Herttuala S, Roberts TC, Turunen MP, Turunen TA. Nuclear microRNA-466c regulates Vegfa expression in response to hypoxia. PLoS One 2022; 17:e0265948. [PMID: 35358280 PMCID: PMC8975276 DOI: 10.1371/journal.pone.0265948] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 03/10/2022] [Indexed: 11/18/2022] Open
Abstract
MicroRNAs are well characterized in their role in silencing gene expression by targeting 3´-UTR of mRNAs in cytoplasm. However, recent studies have shown that miRNAs have a role in the regulation of genes in the nucleus, where they are abundantly located. We show here that in mouse endothelial cell line (C166), nuclear microRNA miR-466c participates in the regulation of vascular endothelial growth factor a (Vegfa) gene expression in hypoxia. Upregulation of Vegfa expression in response to hypoxia was significantly compromised after removal of miR-466c with CRISPR-Cas9 genomic deletion. We identified a promoter-associated long non-coding RNA on mouse Vegfa promoter and show that miR-466c directly binds to this transcript to modulate Vegfa expression. Collectively, these observations suggest that miR-466c regulates Vegfa gene transcription in the nucleus by targeting the promoter, and expands on our understanding of the role of miRNAs well beyond their canonical role.
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Affiliation(s)
- Pia Laitinen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- RNatives Oy, Kuopio, Finland
| | - Mari-Anna Väänänen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Ida-Liisa Kolari
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Petri I. Mäkinen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Minna U. Kaikkonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Marc S. Weinberg
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwaterstrand, Witwaterstrand, South Africa
| | - Kevin V. Morris
- Center for Gene Therapy, City of Hope–Beckman Research Institute at the City of Hope, Duarte, California, United States of America
- Menzies Health Institute Queensland, School of Medical Science Griffith University, Gold Coast Campus, Queensland, Australia
| | - Paula Korhonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Tarja Malm
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
| | - Thomas C. Roberts
- Department of Paediatrics, University of Oxford, Oxford, United Kingdom
- MDUK Oxford Neuromuscular Centre, Oxford, United Kingdom
| | - Mikko P. Turunen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- RNatives Oy, Kuopio, Finland
- * E-mail:
| | - Tiia A. Turunen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- RNatives Oy, Kuopio, Finland
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16
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Between the Devil and the Deep Blue Sea: Non-Coding RNAs Associated with Transmissible Cancers in Tasmanian Devil, Domestic Dog and Bivalves. Noncoding RNA 2021; 7:ncrna7040072. [PMID: 34842768 PMCID: PMC8628904 DOI: 10.3390/ncrna7040072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 12/20/2022] Open
Abstract
Currently there are nine known examples of transmissible cancers in nature. They have been observed in domestic dog, Tasmanian devil, and six bivalve species. These tumours can overcome host immune defences and spread to other members of the same species. Non-coding RNAs (ncRNAs) are known to play roles in tumorigenesis and immune system evasion. Despite their potential importance in transmissible cancers, there have been no studies on ncRNA function in this context to date. Here, we present possible applications of the CRISPR/Cas system to study the RNA biology of transmissible cancers. Specifically, we explore how ncRNAs may play a role in the immortality and immune evasion ability of these tumours.
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17
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Mukherjee S, Detroja R, Balamurali D, Matveishina E, Medvedeva Y, Valencia A, Gorohovski A, Frenkel-Morgenstern M. Computational analysis of sense-antisense chimeric transcripts reveals their potential regulatory features and the landscape of expression in human cells. NAR Genom Bioinform 2021; 3:lqab074. [PMID: 34458728 PMCID: PMC8386243 DOI: 10.1093/nargab/lqab074] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 07/02/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022] Open
Abstract
Many human genes are transcribed from both strands and produce sense-antisense gene pairs. Sense-antisense (SAS) chimeric transcripts are produced upon the coalescing of exons/introns from both sense and antisense transcripts of the same gene. SAS chimera was first reported in prostate cancer cells. Subsequently, numerous SAS chimeras have been reported in the ChiTaRS-2.1 database. However, the landscape of their expression in human cells and functional aspects are still unknown. We found that longer palindromic sequences are a unique feature of SAS chimeras. Structural analysis indicates that a long hairpin-like structure formed by many consecutive Watson-Crick base pairs appears because of these long palindromic sequences, which possibly play a similar role as double-stranded RNA (dsRNA), interfering with gene expression. RNA-RNA interaction analysis suggested that SAS chimeras could significantly interact with their parental mRNAs, indicating their potential regulatory features. Here, 267 SAS chimeras were mapped in RNA-seq data from 16 healthy human tissues, revealing their expression in normal cells. Evolutionary analysis suggested the positive selection favoring sense-antisense fusions that significantly impacted the evolution of their function and structure. Overall, our study provides detailed insight into the expression landscape of SAS chimeras in human cells and identifies potential regulatory features.
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Affiliation(s)
- Sumit Mukherjee
- Cancer Genomics and BioComputing of Complex Diseases Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Rajesh Detroja
- Cancer Genomics and BioComputing of Complex Diseases Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Deepak Balamurali
- Cancer Genomics and BioComputing of Complex Diseases Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Elena Matveishina
- Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119234, Russian Federation
- Institute of Bioengineering, Research Centre of Biotechnology, Russian Academy of Sciences, Moscow 117312, Russian Federation
| | - Yulia A Medvedeva
- Institute of Bioengineering, Research Centre of Biotechnology, Russian Academy of Sciences, Moscow 117312, Russian Federation
- Department of Biomedical Physics, Moscow Institute of Technology, Dolgoprudny 141701, Russian Federation
| | - Alfonso Valencia
- Barcelona Supercomputing Center (BSC), C/ Jordi Girona 29, 08034, Barcelona, Spain
- ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
| | - Alessandro Gorohovski
- Cancer Genomics and BioComputing of Complex Diseases Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
| | - Milana Frenkel-Morgenstern
- Cancer Genomics and BioComputing of Complex Diseases Lab, Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
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18
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Singh N. Role of mammalian long non-coding RNAs in normal and neuro oncological disorders. Genomics 2021; 113:3250-3273. [PMID: 34302945 DOI: 10.1016/j.ygeno.2021.07.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/10/2021] [Accepted: 07/14/2021] [Indexed: 12/09/2022]
Abstract
Long non-coding RNAs (lncRNAs) are expressed at lower levels than protein-coding genes but have a crucial role in gene regulation. LncRNA is distinct, they are being transcribed using RNA polymerase II, and their functionality depends on subcellular localization. Depending on their niche, they specifically interact with DNA, RNA, and proteins and modify chromatin function, regulate transcription at various stages, forms nuclear condensation bodies and nucleolar organization. lncRNAs may also change the stability and translation of cytoplasmic mRNAs and hamper signaling pathways. Thus, lncRNAs affect the physio-pathological states and lead to the development of various disorders, immune responses, and cancer. To date, ~40% of lncRNAs have been reported in the nervous system (NS) and are involved in the early development/differentiation of the NS to synaptogenesis. LncRNA expression patterns in the most common adult and pediatric tumor suggest them as potential biomarkers and provide a rationale for targeting them pharmaceutically. Here, we discuss the mechanisms of lncRNA synthesis, localization, and functions in transcriptional, post-transcriptional, and other forms of gene regulation, methods of lncRNA identification, and their potential therapeutic applications in neuro oncological disorders as explained by molecular mechanisms in other malignant disorders.
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Affiliation(s)
- Neetu Singh
- Molecular Biology Unit, Department of Centre for Advance Research, King George's Medical University, Lucknow, Uttar Pradesh 226 003, India.
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19
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Natural antisense transcript of Period2, Per2AS, regulates the amplitude of the mouse circadian clock. Genes Dev 2021; 35:899-913. [PMID: 34016691 PMCID: PMC8168560 DOI: 10.1101/gad.343541.120] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 04/26/2021] [Indexed: 12/20/2022]
Abstract
In mammals, a set of core clock genes form transcription-translation feedback loops to generate circadian oscillations. We and others recently identified a novel transcript at the Period2 (Per2) locus that is transcribed from the antisense strand of Per2 This transcript, Per2AS, is expressed rhythmically and antiphasic to Per2 mRNA, leading to our hypothesis that Per2AS and Per2 mutually inhibit each other's expression and form a double negative feedback loop. By perturbing the expression of Per2AS, we found that Per2AS transcription, but not transcript, represses Per2 However, Per2 does not repress Per2AS, as Per2 knockdown led to a decrease in the Per2AS level, indicating that Per2AS forms a single negative feedback loop with Per2 and maintains the level of Per2 within the oscillatory range. Per2AS also regulates the amplitude of the circadian clock, and this function cannot be solely explained through its interaction with Per2, as Per2 knockdown does not recapitulate the phenotypes of Per2AS perturbation. Overall, our data indicate that Per2AS is an important regulatory molecule in the mammalian circadian clock machinery. Our work also supports the idea that antisense transcripts of core clock genes constitute a common feature of circadian clocks, as they are found in other organisms.
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20
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Lister NC, Johnsson P, Waters PD, Morris KV. Pseudogenes: A Novel Source of Trans-Acting Antisense RNAs. Methods Mol Biol 2021; 2324:219-236. [PMID: 34165718 DOI: 10.1007/978-1-0716-1503-4_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Several recent studies support a functional role for pseudogenes, a copy of a parent gene that has lost protein-coding potential, which was for a long time thought to represent only "junk" DNA. Several hundreds of pseudogenes have now been reported as transcribed RNAs in a large variety of tissues and tumor types. Most studies have focused on pseudogenes expressed in sense direction, relative to their protein-coding gene counterpart, but some reports suggest that pseudogenes can be also transcribed as antisense RNAs (asRNAs). Key regulatory genes, such as PTEN and OCT4, have in fact been reported to be under the regulation of pseudogene-expressed asRNAs. Here, we review what is known about pseudogene-expressed asRNAs, we discuss the functional role that these transcripts may have in gene regulation and we summarize the techniques that are available to study them.
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Affiliation(s)
- Nicholas C Lister
- School of Biotechnology and Biomedical Sciences, The University of New South Wales, Sydney, NSW, Australia.
| | - Per Johnsson
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Paul D Waters
- School of Biotechnology and Biomedical Sciences, The University of New South Wales, Sydney, NSW, Australia
| | - Kevin V Morris
- Menzies Health Institute and School of Pharmacology and Medical Sciences, Griffith University, Southport, QLD, Australia
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21
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Mahlab-Aviv S, Zohar K, Cohen Y, Peretz AR, Eliyahu T, Linial M, Sperling R. Spliceosome-Associated microRNAs Signify Breast Cancer Cells and Portray Potential Novel Nuclear Targets. Int J Mol Sci 2020; 21:ijms21218132. [PMID: 33143250 PMCID: PMC7663234 DOI: 10.3390/ijms21218132] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/22/2020] [Accepted: 10/28/2020] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) act as negative regulators of gene expression in the cytoplasm. Previous studies have identified the presence of miRNAs in the nucleus. Here we study human breast cancer-derived cell-lines (MCF-7 and MDA-MB-231) and a non-tumorigenic cell-line (MCF-10A) and compare their miRNA sequences at the spliceosome fraction (SF). We report that the levels of miRNAs found in the spliceosome, their identity, and pre-miRNA segmental composition are cell-line specific. One such miRNA is miR-7704 whose genomic position overlaps HAGLR, a cancer-related lncRNA. We detected an inverse expression of miR-7704 and HAGLR in the tested cell lines. Specifically, inhibition of miR-7704 caused an increase in HAGLR expression. Furthermore, elevated levels of miR-7704 slightly altered the cell-cycle in MDA-MB-231. Altogether, we show that SF-miR-7704 acts as a tumor-suppressor gene with HAGLR being its nuclear target. The relative levels of miRNAs found in the spliceosome fractions (e.g., miR-100, miR-30a, and let-7 family) in non-tumorigenic relative to cancer-derived cell-lines was monitored. We found that the expression trend of the abundant miRNAs in SF was different from that reported in the literature and from the observation of large cohorts of breast cancer patients, suggesting that many SF-miRNAs act on targets that are different from the cytoplasmic ones. Altogether, we report on the potential of SF-miRNAs as an unexplored route for cancerous cell state.
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Affiliation(s)
- Shelly Mahlab-Aviv
- Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (S.M.-A.); (K.Z.); (T.E.)
| | - Keren Zohar
- Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (S.M.-A.); (K.Z.); (T.E.)
| | - Yael Cohen
- Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (Y.C.); (A.R.P.)
| | - Ayelet R. Peretz
- Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (Y.C.); (A.R.P.)
| | - Tsiona Eliyahu
- Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (S.M.-A.); (K.Z.); (T.E.)
| | - Michal Linial
- Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (S.M.-A.); (K.Z.); (T.E.)
- Correspondence: (M.L.); (R.S.); Tel.: +972-54-882-0311 (R.S.)
| | - Ruth Sperling
- Department of Genetics, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; (Y.C.); (A.R.P.)
- Correspondence: (M.L.); (R.S.); Tel.: +972-54-882-0311 (R.S.)
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22
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Cruz de Carvalho MH, Bowler C. Global identification of a marine diatom long noncoding natural antisense transcripts (NATs) and their response to phosphate fluctuations. Sci Rep 2020; 10:14110. [PMID: 32839470 PMCID: PMC7445176 DOI: 10.1038/s41598-020-71002-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 08/06/2020] [Indexed: 11/09/2022] Open
Abstract
Often ignored and regarded as mere transcriptional noise, long noncoding RNAs (lncRNAs) are starting to be considered key regulators of gene expression across the Eukarya domain of life. In the model diatom Phaeodactylum tricornutum, we have previously reported the occurrence of 1,510 intergenic lncRNAs (lincRNAs), many of which displaying specific patterns of expression under phosphate fluctuation (Pi). Using strand-specific RNA-sequencing data we now expand the repertoire of P. tricornutum lncRNAs by identifying 2,628 novel natural antisense transcripts (NATs) that cover 21.5% of the annotated genomic loci. We found that NAT expression is tightly regulated by phosphate depletion and other naturally occurring environmental stresses. Furthermore, we identified 121 phosphate stress responsive NAT-mRNA pairs, the great majority of which showing a positive correlation (concordant pairs) and a small fraction with negative correlation (discordant pairs). Taken together our results show that NATs are highly abundant transcripts in P. tricornutum and that their expression is under tight regulation by nutrient and environmental stresses. Furthermore, our results suggest that in P. tricornutum Pi stress response NAT pairs predominantly regulate positively the expression of their cognate sense genes, the latter being involved in several biological processes underlying the control of cellular homeostasis under stress.
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Affiliation(s)
- Maria Helena Cruz de Carvalho
- Institut de Biologie de L'Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, Université PSL, 75005, Paris, France. .,Faculté des sciences et technologie, Université Paris Est-Créteil (UPEC), 94000, Créteil, France.
| | - Chris Bowler
- Institut de Biologie de L'Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, Université PSL, 75005, Paris, France
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23
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Schmidt K, Carroll JS, Yee E, Thomas DD, Wert-Lamas L, Neier SC, Sheynkman G, Ritz J, Novina CD. The lncRNA SLNCR Recruits the Androgen Receptor to EGR1-Bound Genes in Melanoma and Inhibits Expression of Tumor Suppressor p21. Cell Rep 2020; 27:2493-2507.e4. [PMID: 31116991 PMCID: PMC6668037 DOI: 10.1016/j.celrep.2019.04.101] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 04/10/2018] [Accepted: 04/22/2019] [Indexed: 11/30/2022] Open
Abstract
Melanoma is the deadliest form of skin cancer, affecting men more frequently and severely than women. Although recent studies suggest that differences in activity of the androgen receptor (AR) underlie the observed sex bias, little is known about AR activity in melanoma. Here we show that AR and EGR1 bind to the long non-coding RNA SLNCR and increase melanoma proliferation through coordinated transcriptional regulation of several growth-regulatory genes. ChIP-seq reveals that ligand-free AR is enriched on SLNCR-regulated melanoma genes and that AR genomic occupancy significantly overlaps with EGR1 at consensus EGR1 binding sites. We present a model in which SLNCR recruits AR to EGR1-bound genomic loci and switches EGR1-mediated transcriptional activation to repression of the tumor suppressor p21Waf1/Cip1. Our data implicate the regulatory triad of SLNCR, AR, and EGR1 in promoting oncogenesis and may help explain why men have a higher incidence of and more rapidly progressive melanomas compared with women.
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Affiliation(s)
- Karyn Schmidt
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Johanna S Carroll
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Elaine Yee
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Dolly D Thomas
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Leon Wert-Lamas
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Steven C Neier
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA
| | - Gloria Sheynkman
- Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Justin Ritz
- Harvard TH Chan School of Public Health, Boston, MA 02115, USA
| | - Carl D Novina
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
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24
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Wang K, Wang Y, Hu Z, Zhang L, Li G, Dang L, Tan Y, Cao X, Shi F, Zhang S, Zhang G. Bone-targeted lncRNA OGRU alleviates unloading-induced bone loss via miR-320-3p/Hoxa10 axis. Cell Death Dis 2020; 11:382. [PMID: 32427900 PMCID: PMC7237470 DOI: 10.1038/s41419-020-2574-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 01/13/2023]
Abstract
Unloading-induced bone loss is a threat to human health and can eventually result in osteoporotic fractures. Although the underlying molecular mechanism of unloading-induced bone loss has been broadly elucidated, the pathophysiological role of long noncoding RNAs (lncRNAs) in this process is unknown. Here, we identified a novel lncRNA, OGRU, a 1816-nucleotide transcript with significantly decreased levels in bone specimens from hindlimb-unloaded mice and in MC3T3-E1 cells under clinorotation-unloading conditions. OGRU overexpression promoted osteoblast activity and matrix mineralization under normal loading conditions, and attenuated the suppression of MC3T3-E1 cell differentiation induced by clinorotation unloading. Furthermore, this study found that supplementation of pcDNA3.1(+)–OGRU via (DSS)6–liposome delivery to the bone-formation surfaces of hindlimb-unloaded (HLU) mice partially alleviated unloading-induced bone loss. Mechanistic investigations demonstrated that OGRU functions as a competing endogenous RNA (ceRNA) to facilitate the protein expression of Hoxa10 by competitively binding miR-320-3p and subsequently promote osteoblast differentiation and bone formation. Taken together, the results of our study provide the first clarification of the role of lncRNA OGRU in unloading-induced bone loss through the miR-320-3p/Hoxa10 axis, suggesting an efficient anabolic strategy for osteoporosis treatment.
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Affiliation(s)
- Ke Wang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Yixuan Wang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Zebing Hu
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Lijun Zhang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Gaozhi Li
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Lei Dang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yingjun Tan
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China
| | - Xinsheng Cao
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China
| | - Fei Shi
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China.
| | - Shu Zhang
- The Key Laboratory of Aerospace Medicine, Ministry of Education, Air Force Medical University, 710032, Xi'an, Shaanxi, China.
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
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25
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Shang R, Wang M, Dai B, Du J, Wang J, Liu Z, Qu S, Yang X, Liu J, Xia C, Wang L, Wang D, Li Y. Long noncoding RNA SLC2A1-AS1 regulates aerobic glycolysis and progression in hepatocellular carcinoma via inhibiting the STAT3/FOXM1/GLUT1 pathway. Mol Oncol 2020; 14:1381-1396. [PMID: 32174012 PMCID: PMC7266282 DOI: 10.1002/1878-0261.12666] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 03/02/2020] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant diseases worldwide. Despite advances in the diagnosis and treatment of HCC, its overall prognosis remains poor. Recent studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in various pathophysiological processes, including liver cancer. In the current study, we report that lncRNA SLC2A1-AS1 is frequently downregulated in HCC samples, as shown by quantitative real-time polymerase chain reaction analysis. SLC2A1-AS1 deletion is significantly associated with recurrence-free survival in HCC. By performing glucose uptake, lactate production and ATP detection assays, we found that SLC2A1-AS1-mediated glucose transporter 1 (GLUT1) downregulation significantly suppressed glycolysis of HCC. In vitro Cell Counting Kit-8, colony formation, transwell assays as well as in vivo tumorigenesis and metastasis assays showed that SLC2A1-AS1 overexpression significantly suppressed proliferation and metastasis in HCC through the transcriptional inhibition of GLUT1. Results from fluorescence in situ hybridization, ChIP and luciferase reporter assays demonstrated that SLC2A1-AS1 exerts its regulatory role on GLUT1 by competitively binding to transketolase and signal transducer and activator of transcription 3 (STAT3) and inhibits the transactivation of Forkhead box M1 (FOXM1) via STAT3, thus resulting in inactivation of the FOXM1/GLUT1 axis in HCC cells. Our findings will be helpful for understanding the function and mechanism of lncRNA in HCC. These data also highlight the crucial role of SLC2A1-AS1 in HCC aerobic glycolysis and progression and pave the way for further research regarding the potential of SLC2A1-AS1 as a valuable predictive biomarker for HCC recurrence.
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Affiliation(s)
- Runze Shang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Miao Wang
- State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Bin Dai
- Department of General Surgery, General Hospital of the Central Theater Command of the People's Liberation Army, Wuhan, China
| | - Jianbing Du
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Jianlin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Zekun Liu
- State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Shibin Qu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Xisheng Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Jingjing Liu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Congcong Xia
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Desheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi'an, China
| | - Yu Li
- School of Life Science, Northwestern Polytechnical University, Xi'an, China
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26
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Li X, Wang X, Cheng Z, Zhu Q. AGO2 and its partners: a silencing complex, a chromatin modulator, and new features. Crit Rev Biochem Mol Biol 2020; 55:33-53. [DOI: 10.1080/10409238.2020.1738331] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Xiaojing Li
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Xueying Wang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Zeneng Cheng
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
| | - Qubo Zhu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China
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27
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Chen Q, Zhu C, Jin Y. The Oncogenic and Tumor Suppressive Functions of the Long Noncoding RNA MALAT1: An Emerging Controversy. Front Genet 2020; 11:93. [PMID: 32174966 PMCID: PMC7056701 DOI: 10.3389/fgene.2020.00093] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/28/2020] [Indexed: 12/22/2022] Open
Abstract
Long noncoding RNAs are recently emerging as critical factors of tumorigenesis. Originally regarded as a pre-messenger RNA (mRNA) splicing regulator, the long noncoding RNA MALAT1 has been demonstrated to regulate gene transcription by binding histone modification enzymes and transcription factors, and to regulate mRNA and protein expression post-transcriptionally by binding microRNAs (miRNAs) and acting as a sponge. Early studies consistently report that MALAT1 is up-regulated in human cancer tissues of various organ origins, particularly metastatic cancer tissues, that high levels of MALAT1 expression in cancer tissues are associated with poor patient prognosis, and that MALAT1 induces cancer cell proliferation, migration, and invasion in vitro and tumor metastasis in mice. By contrast, by analyzing multiple independent large datasets, MALAT1 have very recently been found to be down-regulated in human colorectal and breast cancer tissues, and low MALAT1 expression is associated with decreased patient survival. By binding to the transcription factor TEAD, MALAT1 suppresses metastasis gene expression, colorectal and breast cancer cell migration, invasion, and metastasis in vitro and in mice. MALAT1 has therefore been proposed to function as a tumor suppressor in colorectal and breast cancers. More comprehensive studies with multiple independent cohorts of human cancer tissues of various organ origins, in vitro and in vivo function, and mechanism studies with rescue experiments are required to confirm the oncogenic or tumor suppressive role of MALAT1 in other cancers.
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Affiliation(s)
- Qingjuan Chen
- Department of Oncology, Yongchuan Hospital, Chongqing Medical University, Chongqing, China
| | - Chenjing Zhu
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yingying Jin
- Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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28
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Zhang F, Ma Y, Xu L, Xu H, Xu Y, Yan N. Long non‑coding RNA profile revealed by microarray indicates that lncCUEDC1 serves a negative regulatory role in breast cancer stem cells. Int J Oncol 2020; 56:807-820. [PMID: 32124947 DOI: 10.3892/ijo.2020.4960] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 11/29/2019] [Indexed: 11/05/2022] Open
Abstract
Previous studies have demonstrated that long non‑coding RNAs (lncRNAs) are involved in breast cancer development, progression and metastasis. However, the association between lncRNAs and breast cancer stem cells (BCSCs) has been poorly explored. To address this issue, microarray analyses were performed to detect the lncRNA profile of BCSCs. In addition, bioinformatics analyses, including Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway analyses, were performed to explore the functional roles of lncRNAs in BCSCs. Lastly, loss of function assays were used to explore the potential function of lncRNA CUE domain containing 1 (lncCUEDC1). A total of 142 differentially expressed lncRNAs were identified. Among these, 25 were downregulated and 117 were upregulated in BCSCs compared with in non‑BCSCs. In addition, the present study revealed that the lncRNAs were largely associated with stemness‑related signaling pathways. Furthermore, it was demonstrated that lncCUEDC1 negatively regulated the phenotype and biological functions of BCSCs in vitro. Mechanistically, lncCUEDC1 could bind NANOG to inhibit the stemness. To the best of our knowledge, the present study was the first to established the lncRNA profile of BCSCs. These findings provided evidence for exploring the functions of lncRNAs in BCSCs and indicated that lncCUEDC1 is a prospective target in BCSCs.
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Affiliation(s)
- Fengchun Zhang
- Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu 215021, P.R. China
| | - Yue Ma
- Department of Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China
| | - Liang Xu
- The First Department of Prevention and Cure Centre of Breast Disease, The Third Hospital of Nanchang City, Nanchang, Jiangxi 330009, P.R. China
| | - Haiyan Xu
- Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu 215021, P.R. China
| | - Yingchun Xu
- Department of Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, P.R. China
| | - Ningning Yan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450002, P.R. China
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29
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DGCR8/ZFAT-AS1 Promotes CDX2 Transcription in a PRC2 Complex-Dependent Manner to Facilitate the Malignant Biological Behavior of Glioma Cells. Mol Ther 2019; 28:613-630. [PMID: 31813799 DOI: 10.1016/j.ymthe.2019.11.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/05/2019] [Accepted: 11/11/2019] [Indexed: 11/24/2022] Open
Abstract
Studies have found that RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are dysregulated and play an important regulatory role in the development of tumors. Based on The Cancer Genome Atlas (TCGA) database, our findings from experiments, and the evidence of previous studies, we screened DiGeorge syndrome critical region gene 8 (DGCR8), ZFAT antisense RNA 1 (ZFAT-AS1), and caudal type homeobox 2 (CDX2) as research candidates. In the present study, DGCR8 and CDX2 were highly expressed and ZFAT-AS1 was markedly downregulated in glioma tissues and cells. DGCR8 or CDX2 knockdown or ZFAT-AS1 overexpression suppressed glioma cell proliferation, migration, and invasion and facilitated apoptosis. DGCR8 might decrease ZFAT-AS1 expression by attenuating its stability in a manner of inducing its cleavage. Importantly, ZFAT-AS1 could inhibit CDX2 transcription by mediating the methylation of histone H3 on lysine 27 (H3K27me3) modification induced by PRC2 in the CDX2 promoter region. In addition, CDX2 transcriptionally activated DGCR8 expression by binding to its promoter regions, forming a positive feedback loop of DGCR8/ZFAT-AS1/CDX2. In conclusion, DGCR8/ZFAT-AS1 promotes CDX2 transcription in a PRC2 complex-dependent manner to facilitate the malignant biological behavior of glioma cells.
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30
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Li LT, Wang X, Zhu WT, Qian GW, Pei DS, Zheng JN. Reciprocal Role Of DNA Methylation And Sp1 Binding In Ki-67 Gene Transcription. Cancer Manag Res 2019; 11:9749-9759. [PMID: 31819613 PMCID: PMC6874502 DOI: 10.2147/cmar.s213769] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 10/16/2019] [Indexed: 01/26/2023] Open
Abstract
Purpose DNA methylation plays major regulatory roles in gene transcription. Our previous studies confirmed that Ki-67 promoter is hypomethylated and Sp1 is a transcriptional activator of Ki-67 gene in cancer cells. However, whether Sp1-mediated transcriptional activation of Ki-67 is related to its methylation has not been studied yet. Materials and methods In this study, we confirmed that methylated CpG binding protein 2 (MBD2) binding to methylated DNA hindered the binding of Sp1 to Ki-67 promoter and then repressed Ki-67 transcription through chromatin immunoprecipitation (ChIP) and quantitative real-time PCR (qRT-PCR). Co-immunoprecipitation (Co-IP), ChIP, methylation-specific PCR (MS-PCR) and Western blot were utilized to analyze the effects of Sp1 binding to Ki-67 promoter on its methylation status. Results Less DNA methyltransferase 1 (DNMT1) bound to the Ki-67 promoter in MKN45 cells than in HK-2 cells. Histone acetyltransferase p300 that was recruited by Sp1 to Ki-67 promoter could attenuate the methylation level of Ki-67 promoter. Furthermore, higher expression of Sp1 and Ki-67 was related to the overall survival (OS), first progression (FP) and post-progression survival (PPS) in gastric cancer by scrutinizing bioinformatics datasets. Conclusion Taken together, our findings suggested that hypomethylation of Ki-67 promoter enhanced the binding of Sp1, which in turn maintained hypomethylation of promoter, leading to increase Ki-67 expression in cancer cells. Sp1 and Ki-67 could act promising prognostic biomarkers for clinical diagnosis and treatment of cancer.
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Affiliation(s)
- Lian-Tao Li
- Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China
| | - Xun Wang
- Department of Interventional Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China
| | - Wen-Tao Zhu
- Department of Pathology, Xuzhou Medical University, Xuzhou 221000, People's Republic of China
| | - Guo-Wei Qian
- Department of Medical Oncology, Shanghai Sixth People's Hospital, Shanghai 200000, People's Republic of China
| | - Dong-Sheng Pei
- Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Department of Pathology, Xuzhou Medical University, Xuzhou 221000, People's Republic of China
| | - Jun-Nian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou 221000, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221000, People's Republic of China
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31
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Kondo S, Kato H, Suzuki Y, Takada T, Eitoku M, Shiroishi T, Suganuma N, Sugano S, Kiyosawa H. Monoallelic, antisense and total RNA transcription in an in vitro neural differentiation system based on F1 hybrid mice. J Cell Sci 2019; 132:jcs.228973. [PMID: 31409693 DOI: 10.1242/jcs.228973] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 08/04/2019] [Indexed: 11/20/2022] Open
Abstract
We developed an in vitro system to differentiate embryonic stem cells (ESCs) derived from reciprocally crossed F1 hybrid mice into neurons, and used it to investigate poly(A)+ and total RNA transcription at different stages of cell differentiation. By comparing expression profiles of transcripts assembled from 20 RNA sequencing datasets [2 alleles×(2 cell lines×4 time-points+2 mouse brains)], the relative influence of strain, cell and parent specificities to overall expression could be assessed. Divergent expression profiles of ESCs converged tightly at neural progenitor stage. Patterns of temporal variation of monoallelically expressed transcripts and antisense transcripts were quantified. Comparison of sense and antisense transcript pairs within the poly(A)+ sample, within the total RNA sample, and across poly(A)+ and total RNA samples revealed distinct rates of pairs showing anti-correlated expression variation. Unique patterns of sharing of poly(A)+ and poly(A)- transcription were identified in distinct RNA species. Regulation and functionality of monoallelic expression, antisense transcripts and poly(A)- transcription remain elusive. We demonstrated the effectiveness of our approach to capture these transcriptional activities, and provided new resources to elucidate the mammalian developmental transcriptome.
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Affiliation(s)
- Shinji Kondo
- Transdisciplinary Research Integration Center, Research Organization of Information and Systems, Tokyo 105-0001, Japan
| | - Hidemasa Kato
- Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan
| | - Toyoyuki Takada
- Transdisciplinary Research Integration Center, Research Organization of Information and Systems, Tokyo 105-0001, Japan.,Mammalian Genetics Laboratory, National Institute of Genetics, Shizuoka 411-8540, Japan
| | - Masamitsu Eitoku
- Department of Environmental Medicine, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
| | - Toshihiko Shiroishi
- Transdisciplinary Research Integration Center, Research Organization of Information and Systems, Tokyo 105-0001, Japan.,Mammalian Genetics Laboratory, National Institute of Genetics, Shizuoka 411-8540, Japan
| | - Narufumi Suganuma
- Department of Environmental Medicine, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
| | - Sumio Sugano
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan
| | - Hidenori Kiyosawa
- Transdisciplinary Research Integration Center, Research Organization of Information and Systems, Tokyo 105-0001, Japan .,Department of Environmental Medicine, Kochi Medical School, Kochi University, Kochi 783-8505, Japan
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32
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Ray RM, Hansen AH, Slott S, Taskova M, Astakhova K, Morris KV. Control of LDL Uptake in Human Cells by Targeting the LDLR Regulatory Long Non-coding RNA BM450697. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 17:264-276. [PMID: 31279228 PMCID: PMC6611981 DOI: 10.1016/j.omtn.2019.05.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/29/2019] [Accepted: 05/29/2019] [Indexed: 10/31/2022]
Abstract
Hypercholesterolemia is a condition that is characterized by very high levels of cholesterol in the blood and is a major correlating factor with heart disease. Indeed, high levels of the low-density lipoprotein (LDL) have been causally linked to the development of atherosclerotic cardiovascular disease (ASCVD). A method to specifically reduce cholesterol in the blood in a long-term, stable manner could prove therapeutically relevant. Cholesterol is removed from the blood by the LDL receptor (LDLR) in the liver. Others and we have discovered that a long non-coding RNA (lncRNA; BM450697) functions as an endogenous epigenetic regulator of LDLR and that the repression of this lncRNA by the action of small interfering RNAs (siRNAs) results in the activation of LDLR. We found here, through the interrogation of two siRNAs that can target this lncRNA, both in a transcriptional and post-transcriptional manner, that BM450697 functions as a local scaffold for modulating LDLR transcription. Moreover, we found that conjugation of α-N-acetylgalactosamine (GalNAc) with two lncRNA-directed siRNAs allows for direct liver cell targeting of this lncRNA and functional enhanced uptake of cholesterol. Collectively, these data suggest that targeting the BM450697 lncRNA regulator of LDLR may result in a more specific, long-term, targeted approach to regulating cholesterol in the blood.
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Affiliation(s)
- Roslyn M Ray
- Center for Gene Therapy, City of Hope, Beckman Research Institute and Hematological Malignancy and Stem Cell Transplantation Institute, 1500 E. Duarte Rd., Duarte, CA, 91010, USA
| | - Anders Højgaard Hansen
- Department of Chemistry, Technical University of Denmark, 206 Kemitorvet, 2800 Kgs Lyngby, Denmark
| | - Sofie Slott
- Department of Chemistry, Technical University of Denmark, 206 Kemitorvet, 2800 Kgs Lyngby, Denmark
| | - Maria Taskova
- Department of Chemistry, Technical University of Denmark, 206 Kemitorvet, 2800 Kgs Lyngby, Denmark
| | - Kira Astakhova
- Department of Chemistry, Technical University of Denmark, 206 Kemitorvet, 2800 Kgs Lyngby, Denmark
| | - Kevin V Morris
- Center for Gene Therapy, City of Hope, Beckman Research Institute and Hematological Malignancy and Stem Cell Transplantation Institute, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.
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33
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Rosikiewicz W, Suzuki Y, Makalowska I. OverGeneDB: a database of 5' end protein coding overlapping genes in human and mouse genomes. Nucleic Acids Res 2019; 46:D186-D193. [PMID: 29069459 PMCID: PMC5753363 DOI: 10.1093/nar/gkx948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 10/20/2017] [Indexed: 01/24/2023] Open
Abstract
Gene overlap plays various regulatory functions on transcriptional and post-transcriptional levels. Most current studies focus on protein-coding genes overlapping with non-protein-coding counterparts, the so called natural antisense transcripts. Considerably less is known about the role of gene overlap in the case of two protein-coding genes. Here, we provide OverGeneDB, a database of human and mouse 5′ end protein-coding overlapping genes. The database contains 582 human and 113 mouse gene pairs that are transcribed using overlapping promoters in at least one analyzed library. Gene pairs were identified based on the analysis of the transcription start site (TSS) coordinates in 73 human and 10 mouse organs, tissues and cell lines. Beside TSS data, resources for 26 human lung adenocarcinoma cell lines also contain RNA-Seq and ChIP-Seq data for seven histone modifications and RNA Polymerase II activity. The collected data revealed that the overlap region is rarely conserved between the studied species and tissues. In ∼50% of the overlapping genes, transcription started explicitly in the overlap regions. In the remaining half of overlapping genes, transcription was initiated both from overlapping and non-overlapping TSSs. OverGeneDB is accessible at http://overgenedb.amu.edu.pl.
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Affiliation(s)
- Wojciech Rosikiewicz
- Department of Integrative Genomics, Institute of Anthropology, Faculty of Biology, Adam Mickiewicz University in Poznan, 61-712 Poznan, Poland
| | - Yutaka Suzuki
- Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 272-8562, Japan
| | - Izabela Makalowska
- Department of Integrative Genomics, Institute of Anthropology, Faculty of Biology, Adam Mickiewicz University in Poznan, 61-712 Poznan, Poland
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Sperling R. Small non-coding RNA within the endogenous spliceosome and alternative splicing regulation. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2019; 1862:194406. [PMID: 31323432 DOI: 10.1016/j.bbagrm.2019.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/08/2019] [Accepted: 07/09/2019] [Indexed: 10/26/2022]
Abstract
Splicing and alternative splicing (AS), which occur in the endogenous spliceosome, play major roles in regulating gene expression, and defects in them are involved in numerous human diseases including cancer. Although the mechanism of the splicing reaction is well understood, the regulation of AS remains to be elucidated. A group of essential regulatory factors in gene expression are small non-coding RNAs (sncRNA): e.g. microRNA, mainly known for their inhibitory role in translation in the cytoplasm; and small nucleolar RNA, known for their role in methylating non-coding RNA in the nucleolus. Here I highlight a new aspect of sncRNAs found within the endogenous spliceosome. Assembled in non-canonical complexes and through different base pairing than their canonical ones, spliceosomal sncRNAs can potentially target different RNAs. Examples of spliceosomal sncRNAs regulating AS, regulating gene expression, and acting in a quality control of AS are reviewed, suggesting novel functions for spliceosomal sncRNAs. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.
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Affiliation(s)
- Ruth Sperling
- Department of Genetics, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
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Laudadio I, Carissimi C, Fulci V. How RNAi machinery enters the world of telomerase. Cell Cycle 2019; 18:1056-1067. [PMID: 31014212 PMCID: PMC6592256 DOI: 10.1080/15384101.2019.1609834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/01/2019] [Accepted: 04/14/2019] [Indexed: 12/27/2022] Open
Abstract
Human telomerase holoenzyme consists of the catalytic component TERT and the template RNA TERC. However, a network of accessory proteins plays key roles in its assembly, localization and stability. Defects in genes involved in telomerase biology affect the renewal of critical stem cell populations and cause disorders such as telomeropathies. Moreover, activation of telomerase in somatic cells allows neoplastic cells to proliferate indefinitely, thus contributing to tumorigenesis. For these reasons, identification of new players involved in telomerase regulation is crucial for the determination of novel therapeutic targets and biomarkers. In the very last years, increasing evidence describes components of the RNAi machinery as a new layer of complexity in human telomerase activity. In this review, we will discuss how AGO2 and other proteins which collaborate with AGO2 in RNAi pathway play a pivotal role in TERC stability and function.
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Affiliation(s)
- Ilaria Laudadio
- Department of Molecular Medicine, “Sapienza” University of Rome, Rome, Italy
| | - Claudia Carissimi
- Department of Molecular Medicine, “Sapienza” University of Rome, Rome, Italy
| | - Valerio Fulci
- Department of Molecular Medicine, “Sapienza” University of Rome, Rome, Italy
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Zhang H, Zhang N, Liu Y, Su P, Liang Y, Li Y, Wang X, Chen T, Song X, Sang Y, Duan Y, Zhang J, Wang L, Chen B, Zhao W, Guo H, Liu Z, Hu G, Yang Q. Epigenetic Regulation of NAMPT by NAMPT-AS
Drives Metastatic Progression in Triple-Negative Breast Cancer. Cancer Res 2019; 79:3347-3359. [PMID: 30940661 DOI: 10.1158/0008-5472.can-18-3418] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/26/2019] [Accepted: 03/29/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Hanwen Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Ning Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Ying Liu
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Peng Su
- Department of Pathology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yiran Liang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yaming Li
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Xiaolong Wang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Tong Chen
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Xiaojin Song
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yuting Sang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Yi Duan
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Jiashu Zhang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Lijuan Wang
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Bing Chen
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Wenjing Zhao
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
| | - Haiyang Guo
- Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada
| | - Zhaojian Liu
- Department of Cell Biology, Shandong University School of Medicine, Jinan, China
| | - Guohong Hu
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China
| | - Qifeng Yang
- Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China.
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji'nan, Shandong, China
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Pu M, Chen J, Tao Z, Miao L, Qi X, Wang Y, Ren J. Regulatory network of miRNA on its target: coordination between transcriptional and post-transcriptional regulation of gene expression. Cell Mol Life Sci 2019; 76:441-451. [PMID: 30374521 PMCID: PMC11105547 DOI: 10.1007/s00018-018-2940-7] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 09/12/2018] [Accepted: 10/08/2018] [Indexed: 12/26/2022]
Abstract
MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that participate in a majority of biological processes via regulating target gene expression. The post-transcriptional repression through miRNA seed region binding to 3' UTR of target mRNA is considered as the canonical mode of miRNA-mediated gene regulation. However, emerging evidence suggests that other regulatory modes exist beyond the canonical mechanism. In particular, the function of intranuclear miRNA in gene transcriptional regulation is gradually revealed, with evidence showing their contribution to gene silencing or activating. Therefore, miRNA-mediated regulation of gene transcription not only expands our understanding of the molecular mechanism underlying miRNA regulatory function, but also provides new evidence to explain its ability in the sophisticated regulation of many bioprocesses. In this review, mechanisms of miRNA-mediated gene transcriptional and post-transcriptional regulation are summarized, and the synergistic effects among these actions which form a regulatory network of a miRNA on its target are particularly elaborated. With these discussions, we aim to emphasize the importance of miRNA regulatory network on target gene regulation and further highlight the potential application of the network mode in the achievement of a more effective and stable modulation of the target gene expression.
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Affiliation(s)
- Mengfan Pu
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
- School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai, 201210, China
| | - Jing Chen
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Zhouteng Tao
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Lingling Miao
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Xinming Qi
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China
| | - Yizheng Wang
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing, 100850, China
| | - Jin Ren
- Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
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Laudadio I, Orso F, Azzalin G, Calabrò C, Berardinelli F, Coluzzi E, Gioiosa S, Taverna D, Sgura A, Carissimi C, Fulci V. AGO2 promotes telomerase activity and interaction between the telomerase components TERT and TERC. EMBO Rep 2018; 20:embr.201845969. [PMID: 30591524 DOI: 10.15252/embr.201845969] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 11/16/2018] [Accepted: 11/26/2018] [Indexed: 12/31/2022] Open
Abstract
Telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) constitute the core telomerase enzyme that maintains the length of telomeres. Telomere maintenance is affected in a broad range of cancer and degenerative disorders. Taking advantage of gain- and loss-of-function approaches, we show that Argonaute 2 (AGO2) promotes telomerase activity and stimulates the association between TERT and TERC AGO2 depletion results in shorter telomeres as well as in lower proliferation rates in vitro and in vivo We also demonstrate that AGO2 interacts with TERC and with a newly identified sRNA (terc-sRNA), arising from the H/ACA box of TERC Notably, terc-sRNA is sufficient to enhance telomerase activity when overexpressed. Analyses of sRNA-Seq datasets show that terc-sRNA is detected in primary human tissues and increases in tumors as compared to control tissues. Collectively, these data uncover a new layer of complexity in the regulation of telomerase activity by AGO2 and might lay the foundation for new therapeutic targets in tumors and telomere diseases.
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Affiliation(s)
- Ilaria Laudadio
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Francesca Orso
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Gianluca Azzalin
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Carlo Calabrò
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | | | - Elisa Coluzzi
- Department of Science, University of Rome "Roma Tre", Rome, Italy
| | - Silvia Gioiosa
- CNR, Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari (IBIOM), Bari, Italy
| | - Daniela Taverna
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Antonella Sgura
- Department of Science, University of Rome "Roma Tre", Rome, Italy
| | - Claudia Carissimi
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Valerio Fulci
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
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Nieminen T, Scott TA, Lin FM, Chen Z, Yla-Herttuala S, Morris KV. Long Non-Coding RNA Modulation of VEGF-A during Hypoxia. Noncoding RNA 2018; 4:ncrna4040034. [PMID: 30463374 PMCID: PMC6315885 DOI: 10.3390/ncrna4040034] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/25/2018] [Accepted: 11/14/2018] [Indexed: 12/17/2022] Open
Abstract
The role and function of long non-coding RNAs (lncRNAs) in modulating gene expression is becoming apparent. Vascular endothelial growth factor A (VEGF-A) is a key regulator of blood vessel formation and maintenance making it a promising therapeutic target for activation in ischemic diseases. In this study, we uncover a functional role for two antisense VEGF-A lncRNAs, RP1-261G23.7 and EST AV731492, in transcriptional regulation of VEGF-A during hypoxia. We find here that both lncRNAs are polyadenylated, concordantly upregulated with VEGF-A, localize to the VEGF-A promoter and upstream elements in a hypoxia dependent manner either as a single-stranded RNA or DNA bound RNA, and are associated with enhancer marks H3K27ac and H3K9ac. Collectively, these data suggest that VEGF-A antisense lncRNAs, RP1-261G23.7 and EST AV731492, function as VEGF-A promoter enhancer-like elements, possibly by acting as a local scaffolding for proteins and also small RNAs to tether.
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Affiliation(s)
- Tiina Nieminen
- The Center for Gene Therapy, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
- Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
| | - Tristan A Scott
- The Center for Gene Therapy, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| | - Feng-Mao Lin
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| | - Zhen Chen
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
| | - Seppo Yla-Herttuala
- Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, FI-70211 Kuopio, Finland.
| | - Kevin V Morris
- The Center for Gene Therapy, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
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Chen H, Shen HX, Lin YW, Mao YQ, Liu B, Xie LP. Small RNA-induced INTS6 gene up-regulation suppresses castration-resistant prostate cancer cells by regulating β-catenin signaling. Cell Cycle 2018; 17:1602-1613. [PMID: 29895194 DOI: 10.1080/15384101.2018.1475825] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
Abstract
Small RNAs play an important role in gene regulatory networks. The gene suppressive effect of small RNAs was previously the dominant focus of studies, but during the recent decade, small RNA-induced gene activation has been reported and has become a notable gene manipulation technique. In this study, a putative tumor suppressor, INTS6, was activated by introducing a promoter-targeted small RNA (dsRNA-915) into castration-resistant prostate cancer (CRPC) cells. Unique dynamics associated with the gene upregulation phenomenon was observed. Following gene activation, cell proliferation and motility were suppressed in vitro. Downregulation of Wnt/β-catenin signaling was observed during the activation period, and the impairment of β-catenin degradation reversed the tumor suppressor effects of INTS6. These results suggest the potential application of small activating RNAs in targeted gene therapy for CRPC.
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Affiliation(s)
- Hong Chen
- a Department of Urology , The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou , Zhejiang Province , China
| | - Hai-Xiang Shen
- a Department of Urology , The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou , Zhejiang Province , China
| | - Yi-Wei Lin
- a Department of Urology , The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou , Zhejiang Province , China
| | - Ye-Qing Mao
- a Department of Urology , The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou , Zhejiang Province , China
| | - Ben Liu
- a Department of Urology , The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou , Zhejiang Province , China
| | - Li-Ping Xie
- a Department of Urology , The First Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou , Zhejiang Province , China
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41
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Yu D, Ma X, Zuo Z, Wang H, Meng Y. Classification of Transcription Boundary-Associated RNAs (TBARs) in Animals and Plants. Front Genet 2018; 9:168. [PMID: 29868116 PMCID: PMC5960741 DOI: 10.3389/fgene.2018.00168] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 04/26/2018] [Indexed: 11/13/2022] Open
Abstract
There is increasing evidence suggesting the contribution of non-coding RNAs (ncRNAs) to the phenotypic and physiological complexity of organisms. A novel ncRNA species has been identified near the transcription boundaries of protein-coding genes in eukaryotes, bacteria, and archaea. This review provides a detailed description of these transcription boundary-associated RNAs (TBARs), including their classification. Based on their genomic distribution, TBARs are divided into two major groups: promoter-associated RNAs (PARs) and terminus-associated RNAs (TARs). Depending on the sequence length, each group is further classified into long RNA species (>200 nt) and small RNA species (<200 nt). According to these rules of TBAR classification, divergent ncRNAs with confusing nomenclatures, such as promoter upstream transcripts (PROMPTs), upstream antisense RNAs (uaRNAs), stable unannotated transcripts (SUTs), cryptic unstable transcripts (CUTs), upstream non-coding transcripts (UNTs), transcription start site-associated RNAs (TSSaRNAs), transcription initiation RNAs (tiRNAs), and transcription termination site-associated RNAs (TTSaRNAs), were assigned to specific classes. Although the biogenesis pathways of PARs and TARs have not yet been clearly elucidated, previous studies indicate that some of the PARs have originated either through divergent transcription or via RNA polymerase pausing. Intriguing findings regarding the functional implications of the TBARs such as the long-range “gene looping” model, which explains their role in the transcriptional regulation of protein-coding genes, are also discussed. Altogether, this review provides a comprehensive overview of the current research status of TBARs, which will promote further investigations in this research area.
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Affiliation(s)
- Dongliang Yu
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
| | - Xiaoxia Ma
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
| | - Ziwei Zuo
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
| | - Huizhong Wang
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
| | - Yijun Meng
- College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China
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42
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Wang XY, Yuan L, Li YL, Gan SJ, Ren L, Zhang F, Jiang J, Qi XW. RNA activation technique and its applications in cancer research. Am J Cancer Res 2018; 8:584-593. [PMID: 29736305 PMCID: PMC5934550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2018] [Accepted: 03/12/2018] [Indexed: 06/08/2023] Open
Abstract
RNA activation (RNAa) is a mechanism of gene activation mediated by small activating RNAs. The activation of gene expression by small activating RNA has excellent targeting specificity and flexibility, with a persistent and strong effect. Studies have shown that the RNAa technique has broad prospects for application in the research on tumor pathogenesis and the treatment of tumors. This paper reviews the literature on RNAa with regard to the course of discovery, the mechanisms and characteristics of action, and the current status and prospects of application.
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Affiliation(s)
- Xiao-Yu Wang
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
| | - Long Yuan
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
| | - Yan-Ling Li
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
| | - Si-Jie Gan
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
| | - Lin Ren
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
| | - Fan Zhang
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
| | - Jun Jiang
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
| | - Xiao-Wei Qi
- Breast Disease Center, Southwest Hospital, Third Military Medical University Chongqing 400038, China
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Jiang Z, Liu H. Metformin inhibits tumorigenesis in HBV-induced hepatocellular carcinoma by suppressing HULC overexpression caused by HBX. J Cell Biochem 2018; 119:4482-4495. [PMID: 29231260 DOI: 10.1002/jcb.26555] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 11/30/2017] [Indexed: 02/06/2023]
Abstract
We aimed to understand whether metformin imposes the inhibitory effect on the HBV-associated tumorigenesis by regulating the HULC and its downstream signaling pathway. Luciferase assay, RT-PCR, and Western-blot, MTT and flow cytometry analysis were performed to understand and the mechanism, by which metformin enhance the inhibitory effect on the HBV-associated tumorigenesis by regulating the HULC and its downstream signaling pathway. HBX promoted viability of three types of cell lines, while metformin inhibited apoptosis of above two cells. ZEB1 was a direct downstream of miR-200a, which was further confirmed that miR-200a reduced luciferase activity of wild-type but not mutant ZEB1 3'UTR, and HULC was bound to region of miR-200a-3p using alignment prediction, but can't affect ZEB1 level. HULC transcription ability, HULC, ZEB1, and p18 levels were much higher in cell treated with HBX, while notably lower in cell treated with metformin, furthermore miR-200a level in cell showed an opposite trend as HULC, ZEB1, and p18 levels. HULC siRNA and miR-200a had no effect on HULC transcription ability, but decreased HULC, ZEB1, and p18 levels, and increased miR-200a expression. HBV (+) HCC +metformin exhibited a higher survival ratio and a lower recurrence rates than HBV (+) HCC group, HBV (-) HCC displayed an even higher survival ratio and an even lower recurrence rates than HBV (+) HCC + metformin groups. This study indicated that metformin imposed inhibitory effect on the HBV-associated HCC by negatively regulating the HULC/p18/miR-200a/ZEB1 signaling pathway.
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Affiliation(s)
- Zhen Jiang
- Department of Gastroenterology, the First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Haichao Liu
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
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Liu MD, Wu H, Wang S, Pang P, Jin S, Sun CF, Liu FY. MiR-1275 promotes cell migration, invasion and proliferation in squamous cell carcinoma of head and neck via up-regulating IGF-1R and CCR7. Gene 2018; 646:1-7. [DOI: 10.1016/j.gene.2017.12.049] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 12/15/2017] [Accepted: 12/22/2017] [Indexed: 12/13/2022]
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45
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Liu H, Lei C, He Q, Pan Z, Xiao D, Tao Y. Nuclear functions of mammalian MicroRNAs in gene regulation, immunity and cancer. Mol Cancer 2018; 17:64. [PMID: 29471827 PMCID: PMC5822656 DOI: 10.1186/s12943-018-0765-5] [Citation(s) in RCA: 248] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 01/12/2018] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding RNAs that contain approximately 22 nucleotides. They serve as key regulators in various biological processes and their dysregulation is implicated in many diseases including cancer and autoimmune disorders. It has been well established that the maturation of miRNAs occurs in the cytoplasm and miRNAs exert post-transcriptional gene silencing (PTGS) via RNA-induced silencing complex (RISC) pathway in the cytoplasm. However, numerous studies reaffirm the existence of mature miRNA in the nucleus, and nucleus-cytoplasm transport mechanism has also been illustrated. Moreover, active regulatory functions of nuclear miRNAs were found including PTGS, transcriptional gene silencing (TGS), and transcriptional gene activation (TGA), in which miRNAs bind nascent RNA transcripts, gene promoter regions or enhancer regions and exert further effects via epigenetic pathways. Based on existing interaction rules, some miRNA binding sites prediction software tools are developed, which are evaluated in this article. In addition, we attempt to explore and review the nuclear functions of miRNA in immunity, tumorigenesis and invasiveness of tumor. As a non-canonical aspect of miRNA action, nuclear miRNAs supplement miRNA regulatory networks and could be applied in miRNA based therapies.
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Affiliation(s)
- Hongyu Liu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- Key Laboratory of Carcinogenesis, Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Cheng Lei
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- Key Laboratory of Carcinogenesis, Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Qin He
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- Key Laboratory of Carcinogenesis, Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Zou Pan
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China
- Key Laboratory of Carcinogenesis, Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, 410078, China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China.
- Key Laboratory of Carcinogenesis, Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan, 410078, China.
- Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, Changsha, China.
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Jung J, Lee S, Cho HS, Park K, Ryu JW, Jung M, Kim J, Kim H, Kim DS. Bioinformatic analysis of regulation of natural antisense transcripts by transposable elements in human mRNA. Genomics 2018; 111:159-166. [PMID: 29366860 DOI: 10.1016/j.ygeno.2018.01.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 01/16/2018] [Accepted: 01/17/2018] [Indexed: 12/19/2022]
Abstract
Non-coding RNA is no longer considered to be "junk" DNA, based on evidence uncovered in recent decades. In particular, the important role played by natural antisense transcripts (NATs) in regulating the expression of genes is receiving increasing attention. However, the regulatory mechanisms of NATs remain incompletely understood. It is well-known that the insertion of transposable elements (TEs) can affect gene transcription. Using a bioinformatics approach, we identified NATs using human mRNA sequences from the UCSC Genome Browser Database. Our in silico analysis identified 1079 NATs and 700 sense-antisense gene pairs. We identified 179 NATs that showed evidence of having been affected by TEs during cellular gene expression. These findings may provide an understanding of the complex regulation mechanisms of NATs. If our understanding of NATs as modulators of gene expression is further enhanced, we can develop ways to control gene expression.
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Affiliation(s)
- Jaeeun Jung
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea; Department of Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Sugi Lee
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea; Department of Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Hyun-Soo Cho
- Department of Stem Cell Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Kunhyang Park
- Department of Core Facility Management Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Jea-Woon Ryu
- Department of Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Minah Jung
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea; Department of Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Jeongkil Kim
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea; Department of Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - HyeRan Kim
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea; Department of Plant Systems Engineering Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea
| | - Dae-Soo Kim
- Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea; Department of Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
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Jiao AL, Foster DJ, Dixon J, Slack FJ. lin-4 and the NRDE pathway are required to activate a transgenic lin-4 reporter but not the endogenous lin-4 locus in C. elegans. PLoS One 2018; 13:e0190766. [PMID: 29324872 PMCID: PMC5764303 DOI: 10.1371/journal.pone.0190766] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 11/27/2017] [Indexed: 11/19/2022] Open
Abstract
As the founding member of the microRNA (miRNA) gene family, insights into lin-4 regulation and function have laid a conceptual foundation for countless miRNA-related studies that followed. We previously showed that a transcriptional lin-4 reporter in C. elegans was positively regulated by a lin-4-complementary element (LCE), and by lin-4 itself. In this study, we sought to (1) identify additional factors required for lin-4 reporter expression, and (2) validate the endogenous relevance of a potential positive autoregulatory mechanism of lin-4 expression. We report that all four core nuclear RNAi factors (nrde-1, nrde-2, nrde-3 and nrde-4), positively regulate lin-4 reporter expression. In contrast, endogenous lin-4 levels were largely unaffected in nrde-2;nrde-3 mutants. Further, an endogenous LCE deletion generated by CRISPR-Cas9 revealed that the LCE was also not necessary for the activity of the endogenous lin-4 promoter. Finally, mutations in mature lin-4 did not reduce primary lin-4 transcript levels. Taken together, these data indicate that under growth conditions that reveal effects at the transgenic locus, a direct, positive autoregulatory mechanism of lin-4 expression does not occur in the context of the endogenous lin-4 locus.
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Affiliation(s)
- Alan L. Jiao
- Institute for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT United States of America
| | - Daniel J. Foster
- Institute for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
- Department of Biological and Biomedical Sciences, Harvard University, Boston, MA, United States of America
| | - Julia Dixon
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT United States of America
| | - Frank J. Slack
- Institute for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
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Wang L, Liu Y, Sun S, Lu M, Xia Y. Regulation of neuronal-glial fate specification by long non-coding RNAs. Rev Neurosci 2018; 27:491-9. [PMID: 26943605 DOI: 10.1515/revneuro-2015-0061] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/06/2016] [Indexed: 12/20/2022]
Abstract
Neural stem cell transplantation is becoming a promising and attractive cell-based treatment modality for repairing the damaged central nervous system. One of the limitations of this approach is that the proportion of functional cells differentiated from stem cells still remains at a low level. In recent years, novel long non-coding RNAs (lncRNAs) are being discovered at a growing pace, suggesting that this class of molecules may act as novel regulators in neuronal-glial fate specification. In this review, we first describe the general features of lncRNAs that are more likely to be relevant to reveal their function. By this, we aim to point out the specific roles of a number of lncRNAs whose function has been described during neuronal and glial cell differentiation. There is no doubt that investigation of the lncRNAs will open a new window in studying neuronal-glial fate specification.
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Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and lethal neurodegenerative diseases seen comorbidly in up to 15% of patients. Despite several decades of research, no effective treatment or disease-modifying strategies have been developed. We now understand more than before about the genetics and biology behind ALS and FTD, but the genetic etiology for the majority of patients is still unknown and the phenotypic variability observed across patients, even those carrying the same mutation, is enigmatic. Additionally, susceptibility factors leading to neuronal vulnerability in specific central nervous system regions involved in disease are yet to be identified. As the inherited but dynamic epigenome acts as a cell-specific interface between the inherited fixed genome and both cell-intrinsic mechanisms and environmental input, adaptive epigenetic changes might contribute to the ALS/FTD aspects we still struggle to comprehend. This chapter summarizes our current understanding of basic epigenetic mechanisms, how they relate to ALS and FTD, and their potential as therapeutic targets. A clear understanding of the biological mechanisms driving these two currently incurable diseases is urgent-well-needed therapeutic strategies need to be developed soon. Disease-specific epigenetic changes have already been observed in patients and these might be central to this endeavor.
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Affiliation(s)
- Mark T W Ebbert
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - Rebecca J Lank
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA
| | - Veronique V Belzil
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. .,Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
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Comprehensive Identification of Nuclear and Cytoplasmic TNRC6A-Associating Proteins. J Mol Biol 2017; 429:3319-3333. [DOI: 10.1016/j.jmb.2017.04.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 04/18/2017] [Accepted: 04/24/2017] [Indexed: 11/20/2022]
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