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1
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Zhou L, Li H, Sun T, Wen X, Niu C, Li M, Li W, Esteban MA, Hoffman AR, Hu JF, Cui J. Profiling mitochondria-polyribosome lncRNAs associated with pluripotency. Sci Data 2023; 10:755. [PMID: 37919270 PMCID: PMC10622415 DOI: 10.1038/s41597-023-02649-3] [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: 12/01/2022] [Accepted: 10/16/2023] [Indexed: 11/04/2023] Open
Abstract
Pluripotent stem cells (PSCs) provide unlimited resources for regenerative medicine because of their potential for self-renewal and differentiation into many different cell types. The pluripotency of these PSCs is dynamically regulated at multiple cellular organelle levels. To delineate the factors that coordinate this inter-organelle crosstalk, we profiled those long non-coding RNAs (lncRNAs) that may participate in the regulation of multiple cellular organelles in PSCs. We have developed a unique strand-specific RNA-seq dataset of lncRNAs that may interact with mitochondria (mtlncRNAs) and polyribosomes (prlncRNAs). Among the lncRNAs differentially expressed between induced pluripotent stem cells (iPSCs), fibroblasts, and positive control H9 human embryonic stem cells, we identified 11 prlncRNAs related to stem cell reprogramming and exit from pluripotency. In conjunction with the total RNA-seq data, this dataset provides a valuable resource to examine the role of lncRNAs in pluripotency, particularly for studies investigating the inter-organelle crosstalk network involved in germ cell development and human reproduction.
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Affiliation(s)
- Lei Zhou
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China.
| | - Hui Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China
| | - Tingge Sun
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China
| | - Xue Wen
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China
| | - Chao Niu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China
| | - Min Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China
| | - Wei Li
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China
| | - Miguel A Esteban
- Laboratory of Integrative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Andrew R Hoffman
- Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA
| | - Ji-Fan Hu
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China.
- Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
| | - Jiuwei Cui
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Cancer Center, First Hospital of Jilin University, Changchun, Jilin, 130061, P.R. China.
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Aich M, Ansari AH, Ding L, Iesmantavicius V, Paul D, Choudhary C, Maiti S, Buchholz F, Chakraborty D. TOBF1 modulates mouse embryonic stem cell fate through regulating alternative splicing of pluripotency genes. Cell Rep 2023; 42:113177. [PMID: 37751355 DOI: 10.1016/j.celrep.2023.113177] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/28/2023] [Accepted: 09/11/2023] [Indexed: 09/28/2023] Open
Abstract
Embryonic stem cells (ESCs) can undergo lineage-specific differentiation, giving rise to different cell types that constitute an organism. Although roles of transcription factors and chromatin modifiers in these cells have been described, how the alternative splicing (AS) machinery regulates their expression has not been sufficiently explored. Here, we show that the long non-coding RNA (lncRNA)-associated protein TOBF1 modulates the AS of transcripts necessary for maintaining stem cell identity in mouse ESCs. Among the genes affected is serine/arginine splicing factor 1 (SRSF1), whose AS leads to global changes in splicing and expression of a large number of downstream genes involved in the maintenance of ESC pluripotency. By overlaying information derived from TOBF1 chromatin occupancy, the distribution of its pluripotency-associated OCT-SOX binding motifs, and transcripts undergoing differential expression and AS upon its knockout, we describe local nuclear territories where these distinct events converge. Collectively, these contribute to the maintenance of mouse ESC identity.
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Affiliation(s)
- Meghali Aich
- CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Asgar Hussain Ansari
- CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Li Ding
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Vytautas Iesmantavicius
- The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Deepanjan Paul
- CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India
| | - Chunaram Choudhary
- The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Souvik Maiti
- CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Frank Buchholz
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Debojyoti Chakraborty
- CSIR- Institute of Genomics and Integrative Biology, New Delhi 110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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3
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Hong H, Zeng K, Zhou C, Chen X, Xu Z, Li M, Liu L, Zeng Q, Tao Q, Wei X. The pluripotent factor OCT4A enhances the self-renewal of human dental pulp stem cells by targeting lncRNA FTX in an LPS-induced inflammatory microenvironment. Stem Cell Res Ther 2023; 14:109. [PMID: 37106382 PMCID: PMC10142416 DOI: 10.1186/s13287-023-03313-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 03/29/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND Regulating the pluripotency of human dental pulp stem cells (hDPSCs) is key for the self-repair of injured dental pulp. We previously found that OCT4A promotes the proliferation and odontogenic differentiation of human dental pulp cells (hDPCs). Recent studies have shown the interaction between OCT4A and lncRNAs in pluripotency maintenance of various stem cells. The aim of this study was to explore the underlying roles and mechanisms of OCT4A and its related lncRNAs in the proliferation and multidirectional differentiation of hDPSCs in an inflammatory microenvironment. METHODS Human lncRNA microarrays were applied to screen out the differentially expressed lncRNAs in hDPSCs between the OCT4A-overexpressing and vector groups. Lipopolysaccharide (LPS) was used to simulate the inflammatory microenvironment. The effects of OCT4A and the lncRNA FTX on the proliferation and multidifferentiation of hDPSCs were observed by the CCK-8 assay, EdU staining, real-time PCR, western blotting, and Alizarin red and oil red O staining. Bioinformatics analysis and chromatin immunoprecipitation (ChIP) assays were performed to clarify the targeted mechanism of OCT4A on FTX. The regulation by FTX of the expression of OCT4A and its downstream pluripotent transcription factors SOX2 and c-MYC was further detected by real-time PCR and western blotting. RESULTS The microarray results showed that 978 lncRNAs (250 of which were upregulated and 728 downregulated) were potentially differentially expressed genes (fold change ≥ 2, P < 0.05). LPS stimulation attenuated the self-renewal of hDPSCs. OCT4A enhanced the cell proliferation and multidifferentiation capacities of hDPSCs in an inflammatory microenvironment, while FTX exhibited the opposite effects. OCT4A negatively regulated FTX function by binding to specific regions on the FTX promoter, thereby inhibiting the transcription of FTX. Moreover, overexpression of FTX downregulated the expression of OCT4A, SOX2 and c-MYC, whereas knockdown of FTX facilitated their expression. CONCLUSIONS OCT4A was found to be a crucial factor maintaining the self-renewal of hDPSCs by transcriptionally targeting FTX in an inflammatory microenvironment. Moreover, we proposed a novel function of FTX in negatively regulating the pluripotency and multilineage differentiation capacity of hDPSCs. The hierarchical organization between OCT4A and FTX expanded the understanding of the network between transcription factors and lncRNAs in fine-tuning the pluripotency/differentiation balance of adult stem cells, and provided prospective targets for optimizing dental-derived stem cell sources for regenerative endodontics.
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Affiliation(s)
- Hong Hong
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Kai Zeng
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Can Zhou
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Xiaochuan Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Zhezhen Xu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Mengjie Li
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Lu Liu
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Qian Zeng
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China
| | - Qian Tao
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China.
| | - Xi Wei
- Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, People's Republic of China.
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Jafari-Raddani F, Davoodi-Moghaddam Z, Yousefi AM, Ghaffari SH, Bashash D. An overview of long noncoding RNAs: Biology, functions, therapeutics, analysis methods, and bioinformatics tools. Cell Biochem Funct 2022; 40:800-825. [PMID: 36111699 DOI: 10.1002/cbf.3748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 12/15/2022]
Abstract
Long noncoding RNAs (lncRNAs) are a diverse class of RNAs whose functions are widespread in all branches of life and have been the focus of attention in the last decade. While a huge number of lncRNAs have been identified, there is still much work to be done and plenty to be learned. In the current review, we begin with the biogenesis and function of lncRNAs as they are involved in the different cellular processes from regulating the architecture of chromosomes to controlling translation and post-translation modifications. Questions on how overexpression, mutations, or deficiency of lncRNAs can affect the cellular status and result in the pathogenesis of various human diseases are responded to. Besides, we allocate an overview of several studies, concerning the application of lncRNAs either as diagnostic and prognostic biomarkers or novel therapeutics. We also introduce the currently available techniques to explore details of lncRNAs such as their function, cellular localization, and structure. In the last section, as exponentially growing data in this area need to be gathered and organized in comprehensive databases, we have a particular focus on presenting general and specialized databases. Taken together, with this review, we aim to provide the latest information on different aspects of lncRNAs to highlight their importance in physiopathologic states and take a step towards helping future studies.
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Affiliation(s)
- Farideh Jafari-Raddani
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeinab Davoodi-Moghaddam
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir-Mohammad Yousefi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Xie D, Tong M, Xia B, Feng G, Wang L, Li A, Luo G, Wan H, Zhang Z, Zhang H, Yang YG, Zhou Q, Wang M, Wang XJ. Long noncoding RNA lnc-NAP sponges mmu-miR-139-5p to modulate Nanog functions in mouse ESCs and embryos. RNA Biol 2021; 18:875-887. [PMID: 32991228 PMCID: PMC8081037 DOI: 10.1080/15476286.2020.1827591] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/30/2020] [Accepted: 09/20/2020] [Indexed: 12/30/2022] Open
Abstract
The pluripotency of embryonic stem cells (ESCs) is controlled by a multilayer regulatory network, of which the key factors include core pluripotency genes Oct4, Sox2 and Nanog, and multiple microRNAs (miRNAs). Recently, long noncoding RNAs (lncRNAs) have been discovered as a class of new regulators for ESCs, and some lncRNAs could function as competing endogenous RNAs (ceRNAs) to regulate mRNAs by competitively binding to miRNAs. Here, we identify mmu-miR-139-5p as a new regulator for Nanog by targeting Nanog 3' untranslated region (UTR) to repress Nanog expression in mouse ESCs and embryos. Such regulation could be released by an ESC-specifically expressed ceRNA named lnc-NAP. The expression of lnc-NAP is activated by OCT4, SOX2, as well as NANOG through promoter binding. Downregulation of lnc-NAP reduces Nanog abundance, which leads to decreased pluripotency of mouse ESCs and embryonic lethality. These results reveal lnc-NAP as a new regulator for Nanog in mouse ESCs, and uncover a feed-forward regulatory loop of Nanog through the participation of lnc-NAP.
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MESH Headings
- 3' Untranslated Regions/genetics
- Animals
- Cell Differentiation/genetics
- Embryo, Mammalian/cytology
- Embryo, Mammalian/embryology
- Embryo, Mammalian/metabolism
- Embryonic Stem Cells/cytology
- Embryonic Stem Cells/metabolism
- Gene Expression Regulation, Developmental
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Inbred NOD
- Mice, SCID
- MicroRNAs/genetics
- Nanog Homeobox Protein/genetics
- Nanog Homeobox Protein/metabolism
- Octamer Transcription Factor-3/genetics
- Octamer Transcription Factor-3/metabolism
- Promoter Regions, Genetic/genetics
- Protein Binding
- RNA, Long Noncoding/genetics
- RNA-Seq/methods
- Reverse Transcriptase Polymerase Chain Reaction/methods
- SOXB1 Transcription Factors/genetics
- SOXB1 Transcription Factors/metabolism
- Mice
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Affiliation(s)
- Dongfang Xie
- Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China
| | - Man Tong
- Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China
| | - Baolong Xia
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Guihai Feng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Leyun Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Ang Li
- University of Chinese Academy of Sciences, Beijing, China
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Guanzheng Luo
- Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China
| | - Haifeng Wan
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Zeyu Zhang
- Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China
| | - Hao Zhang
- Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China
| | - Yun-Gui Yang
- University of Chinese Academy of Sciences, Beijing, China
- Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Meng Wang
- Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China
| | - Xiu-Jie Wang
- Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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6
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Decoding LncRNAs. Cancers (Basel) 2021; 13:cancers13112643. [PMID: 34072257 PMCID: PMC8199187 DOI: 10.3390/cancers13112643] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
Non-coding RNAs (ncRNAs) have been considered as unimportant additions to the transcriptome. Yet, in light of numerous studies, it has become clear that ncRNAs play important roles in development, health and disease. Long-ignored, long non-coding RNAs (lncRNAs), ncRNAs made of more than 200 nucleotides have gained attention due to their involvement as drivers or suppressors of a myriad of tumours. The detailed understanding of some of their functions, structures and interactomes has been the result of interdisciplinary efforts, as in many cases, new methods need to be created or adapted to characterise these molecules. Unlike most reviews on lncRNAs, we summarize the achievements on lncRNA studies by taking into consideration the approaches for identification of lncRNA functions, interactomes, and structural arrangements. We also provide information about the recent data on the involvement of lncRNAs in diseases and present applications of these molecules, especially in medicine.
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7
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Hansen J, von Melchner H, Wurst W. Mutant non-coding RNA resource in mouse embryonic stem cells. Dis Model Mech 2021; 14:14/2/dmm047803. [PMID: 33729986 PMCID: PMC7875499 DOI: 10.1242/dmm.047803] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/14/2020] [Indexed: 01/23/2023] Open
Abstract
Gene trapping is a high-throughput approach that has been used to introduce insertional mutations into the genome of mouse embryonic stem (ES) cells. It is performed with generic gene trap vectors that simultaneously mutate and report the expression of the endogenous gene at the site of insertion and provide a DNA sequence tag for the rapid identification of the disrupted gene. Large-scale international efforts assembled a gene trap library of 566,554 ES cell lines with single gene trap integrations distributed throughout the genome. Here, we re-investigated this unique library and identified mutations in 2202 non-coding RNA (ncRNA) genes, in addition to mutations in 12,078 distinct protein-coding genes. Moreover, we found certain types of gene trap vectors preferentially integrating into genes expressing specific long non-coding RNA (lncRNA) biotypes. Together with all other gene-trapped ES cell lines, lncRNA gene-trapped ES cell lines are readily available for functional in vitro and in vivo studies.
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Affiliation(s)
- Jens Hansen
- Institute of Developmental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany
| | - Harald von Melchner
- Department of Molecular Hematology, University Hospital Frankfurt, Goethe University, D-60590 Frankfurt am Main, Germany
| | - Wolfgang Wurst
- Institute of Developmental Genetics, Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany .,Technische Universität München-Weihenstephan, c/o Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany.,German Center for Neurodegenerative Diseases (DZNE), Site Munich, Feodor-Lynen-Str. 17, D-81377 Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 17, D-81377 München, Germany
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8
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Zhu Y, Yan Z, Tang Z, Li W. Novel Approaches to Profile Functional Long Noncoding RNAs Associated with Stem Cell Pluripotency. Curr Genomics 2020; 21:37-45. [PMID: 32655297 PMCID: PMC7324891 DOI: 10.2174/1389202921666200210142840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/17/2020] [Accepted: 01/31/2020] [Indexed: 12/11/2022] Open
Abstract
The pluripotent state of stem cells depends on the complicated network orchestrated by thousands of factors and genes. Long noncoding RNAs (lncRNAs) are a class of RNA longer than 200 nt without a protein-coding function. Single-cell sequencing studies have identified hundreds of lncRNAs with dynamic changes in somatic cell reprogramming. Accumulating evidence suggests that they participate in the initiation of reprogramming, maintenance of pluripotency, and developmental processes by cis and/or trans mechanisms. In particular, they may interact with proteins, RNAs, and chromatin modifier complexes to form an intricate pluripotency-associated network. In this review, we focus on recent progress in approaches to profiling functional lncRNAs in somatic cell reprogramming and cell differentiation.
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Affiliation(s)
- Yanbo Zhu
- 1Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin130021, China; 2Division of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin130021, China; 3Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, China
| | - Zi Yan
- 1Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin130021, China; 2Division of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin130021, China; 3Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, China
| | - Ze Tang
- 1Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin130021, China; 2Division of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin130021, China; 3Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, China
| | - Wei Li
- 1Stem Cell and Cancer Center, The First Hospital of Jilin University, Changchun, Jilin130021, China; 2Division of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin130021, China; 3Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin130021, China
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9
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Abstract
Embryonic Stem cells are widely studied to elucidate the disease and developmental processes because of their capability to differentiate into cells of any lineage, Pervasive transcription is a distinct feature of all multicellular organisms and genomic elements such as enhancers and bidirectional or unidirectional promoters regulate these processes. Thousands of loci in each species produce a class of transcripts called noncoding RNAs (ncRNAs), that are well known for their influential regulatory roles in multiple biological processes including stem cell pluripotency and differentiation. The number of lncRNA species increases in more complex organisms highlighting the importance of RNA-based control in the evolution of multicellular organisms. Over the past decade, numerous studies have shed light on lncRNA biogenesis and functional significance in the cell and the organism. In this review, we focus primarily on lncRNAs affecting the stem cell state and developmental pathways.
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Affiliation(s)
- Meghali Aich
- CSIR-Institute of Genomics & Integrative Biology, New Delhi, India; Academy of Scientific & Innovative Research, New Delhi, India
| | - Debojyoti Chakraborty
- CSIR-Institute of Genomics & Integrative Biology, New Delhi, India; Academy of Scientific & Innovative Research, New Delhi, India.
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10
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Liu N, Wang ZZ, Zhao M, Zhang Y, Chen NH. Role of non-coding RNA in the pathogenesis of depression. Gene 2019; 735:144276. [PMID: 31816363 DOI: 10.1016/j.gene.2019.144276] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/19/2019] [Accepted: 11/19/2019] [Indexed: 12/20/2022]
Abstract
Depression is increasingly threatening human health as a serious psychological problem. However, it is remarkable that the precise mechanism underlying depression remains unelucidated. Recent studies have clarified that non-coding RNA, including but not limited to microRNA, long non-coding RNA, and circular RNA, plays an important role in the pathogenesis of depression. The research results cited in this paper reveal the origin, expression, distribution, function, and mechanism of microRNA in the nervous system. MicroRNA is involved in regulation of life activities, including growth, immune reaction, haematopoiesis, and metabolism, which are significant for maintaining normal physiological functions. Moreover, microRNA plays an important role in cell death and proliferation, development of cancer, and disease prognosis. Here, we also introduce the general research status of long non-coding RNA and circular RNA. Next, descriptive study methods, including fluorescence quantitative polymerase chain reaction, northern blot, microarray technology, RNA-seq, and fluorescent in situ hybridization are discussed. Functional study methods are also summarized and divided into gain- and loss-of-function studies. Moreover, the roles of non-coding RNA in the pathogenesis of depression, including neurogenesis, synaptic plasticity, brain-derived neurotrophic factor expression, HPA axis regulation, neurotransmission, neuropeptide expression, neuro-inflammation, and polyamine synthesis are discussed. Nevertheless, many unknown associations between non-coding RNA and depression remain to be clarified.
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Affiliation(s)
- Nuo Liu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zhen-Zhen Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Ming Zhao
- Department of Pharmacy, Beijing Hospital, National Center of Gerontology, Beijing 100730, China
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Nai-Hong Chen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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11
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Sun B, Liu C, Li H, Zhang L, Luo G, Liang S, Lü M. Research progress on the interactions between long non-coding RNAs and microRNAs in human cancer. Oncol Lett 2019; 19:595-605. [PMID: 31897175 PMCID: PMC6923957 DOI: 10.3892/ol.2019.11182] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 11/12/2019] [Indexed: 12/17/2022] Open
Abstract
Numerous types of molecular mechanisms mediate the development of cancer. Non-coding RNAs (ncRNAs) are being increasingly recognized to play important role in mediating the development of diseases, including cancer. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are the two most widely studied ncRNAs. Thus far, lncRNAs are known to have biological roles through a variety of mechanisms, including genetic imprinting, chromatin remodeling, cell cycle control, splicing regulation, mRNA decay and translational regulation, and miRNAs regulate gene expression through the degradation of mRNAs and lncRNAs. Although ncRNAs account for a major proportion of the total RNA, the mechanisms underlying the physiological or pathological processes mediated by various types of ncRNAs, and the specific interaction mechanisms between miRNAs and lncRNAs in various physiological and pathological processes, remain largely unknown. Thus, further research in this field is required. In general, the interaction mechanisms between miRNAs and lncRNAs in human cancer have become important research topics, and the study thereof has led to the recent development of related technologies. By providing examples and descriptions, and performing chart analysis, the present study aimed to review the interaction mechanisms and research approaches for these two types of ncRNAs, as well as their roles in the occurrence and development of cancer. These details have far-reaching significance for the utilization of these molecules in the diagnosis and treatment of cancer.
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Affiliation(s)
- Binyu Sun
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Chunxia Liu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Hao Li
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Lu Zhang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Gang Luo
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Sicheng Liang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Muhan Lü
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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12
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Shields EJ, Petracovici AF, Bonasio R. lncRedibly versatile: biochemical and biological functions of long noncoding RNAs. Biochem J 2019; 476:1083-1104. [PMID: 30971458 PMCID: PMC6745715 DOI: 10.1042/bcj20180440] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 02/28/2019] [Accepted: 03/19/2019] [Indexed: 02/07/2023]
Abstract
Long noncoding RNAs (lncRNAs) are transcripts that do not code for proteins, but nevertheless exert regulatory effects on various biochemical pathways, in part via interactions with proteins, DNA, and other RNAs. LncRNAs are thought to regulate transcription and other biological processes by acting, for example, as guides that target proteins to chromatin, scaffolds that facilitate protein-protein interactions and complex formation, and orchestrators of phase-separated compartments. The study of lncRNAs has reached an exciting time, as recent advances in experimental and computational methods allow for genome-wide interrogation of biochemical and biological mechanisms of these enigmatic transcripts. A better appreciation for the biochemical versatility of lncRNAs has allowed us to begin closing gaps in our knowledge of how they act in diverse cellular and organismal contexts, including development and disease.
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Affiliation(s)
- Emily J Shields
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, U.S.A
- Graduate Group in Genomics and Computational Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, U.S.A
| | - Ana F Petracovici
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, U.S.A
- Graduate Group in Genetics and Epigenetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, U.S.A
| | - Roberto Bonasio
- Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, U.S.A.
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, U.S.A
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13
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Charles Richard JL, Eichhorn PJA. Platforms for Investigating LncRNA Functions. SLAS Technol 2018; 23:493-506. [PMID: 29945466 PMCID: PMC6249642 DOI: 10.1177/2472630318780639] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/04/2018] [Accepted: 05/14/2018] [Indexed: 01/09/2023]
Abstract
Prior to the sequencing of the human genome, it was presumed that most of the DNA coded for proteins. However, with the advent of next-generation sequencing, it has now been recognized that most complex eukaryotic genomes are in fact transcribed into noncoding RNAs (ncRNAs), including a family of transcripts referred to as long noncoding RNAs (lncRNAs). LncRNAs have been implicated in many biological processes ranging from housekeeping functions such as transcription to more specialized functions such as dosage compensation or genomic imprinting, among others. Interestingly, lncRNAs are not limited to a defined set of functions but can regulate varied activities such as messenger RNA degradation, translation, and protein kinetics or function as RNA decoys or scaffolds. Although still in its infancy, research into the biology of lncRNAs has demonstrated the importance of lncRNAs in development and disease. However, the specific mechanisms through which these lncRNAs act remain poorly defined. Focused research into a small number of these lncRNAs has provided important clues into the heterogeneous nature of this family of ncRNAs. Due to the complex diversity of lncRNA function, in this review, we provide an update on the platforms available for investigators to aid in the identification of lncRNA function.
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Affiliation(s)
- John Lalith Charles Richard
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Genome Institute of Singapore, Agency for Science Technology and Research, Singapore
| | - Pieter Johan Adam Eichhorn
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia
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14
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Xu J, Shi A, Long Z, Xu L, Liao G, Deng C, Yan M, Xie A, Luo T, Huang J, Xiao Y, Li X. Capturing functional long non-coding RNAs through integrating large-scale causal relations from gene perturbation experiments. EBioMedicine 2018; 35:369-380. [PMID: 30177244 PMCID: PMC6156711 DOI: 10.1016/j.ebiom.2018.08.050] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 08/15/2018] [Accepted: 08/22/2018] [Indexed: 02/06/2023] Open
Abstract
Characterizing functions of long noncoding RNAs (lncRNAs) remains a major challenge, mostly due to the lack of lncRNA-involved regulatory relationships. A wide array of genome-wide expression profiles generated by gene perturbation have been widely used to capture causal links between perturbed genes and response genes. Through annotating >600 gene perturbation profiles, over 354,000 causal relationships between perturbed genes and lncRNAs were identified. This large-scale resource of causal relations inspired us to develop a novel computational approach LnCAR for inferring lncRNAs' functions, which showed a higher accuracy than the co-expression based approach. By application of LnCAR to the cancer hallmark processes, we identified 38 lncRNAs involved in distinct carcinogenic processes. The "activating invasion & metastasis" related lncRNAs were strongly associated with metastatic progression in various cancer types and could act as a predictor of cancer metastasis. Meanwhile, the "evading immune destruction" related lncRNAs showed significant associations with immune infiltration of various immune cells and, importantly, can predict response to anti-PD-1 immunotherapy, suggesting their potential roles as biomarkers for immune therapy. Taken together, our approach provides a novel way to systematically reveal functions of lncRNAs, which will be helpful for further experimental exploration and clinical translational research of lncRNAs.
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Affiliation(s)
- Jinyuan Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Aiai Shi
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Zhilin Long
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Liwen Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Gaoming Liao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Chunyu Deng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Min Yan
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Aiming Xie
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Tao Luo
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China
| | - Jian Huang
- Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 611731, China.
| | - Yun Xiao
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China; Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Harbin, Heilongjiang 150086, China.
| | - Xia Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China; Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Harbin, Heilongjiang 150086, China.
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15
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Chakraborty D, Paszkowski-Rogacz M, Berger N, Ding L, Mircetic J, Fu J, Iesmantavicius V, Choudhary C, Anastassiadis K, Stewart AF, Buchholz F. lncRNA Panct1 Maintains Mouse Embryonic Stem Cell Identity by Regulating TOBF1 Recruitment to Oct-Sox Sequences in Early G1. Cell Rep 2018; 21:3012-3021. [PMID: 29241531 DOI: 10.1016/j.celrep.2017.11.045] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 10/13/2017] [Accepted: 11/13/2017] [Indexed: 11/25/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) have been implicated in diverse biological processes, including embryonic stem cell (ESC) maintenance. However, their functional mechanisms remain largely undefined. Here, we show that the lncRNA Panct1 regulates the transient recruitment of a putative X-chromosome-encoded protein A830080D01Rik, hereafter referred to as transient octamer binding factor 1 (TOBF1), to genomic sites resembling the canonical Oct-Sox motif. TOBF1 physically interacts with Panct1 and exhibits a cell-cycle-specific punctate localization in ESCs. At the chromatin level, this correlates with its recruitment to promoters of pluripotency genes. Strikingly, mutating an octamer-like motif in Panct1 RNA abrogates the strength of TOBF1 localization and recruitment to its targets. Taken together, our data reveal a tightly controlled spatial and temporal pattern of lncRNA-mediated gene regulation in a cell-cycle-dependent manner and suggest that lncRNAs might function as barcodes for identifying genomic addresses for maintaining cellular states.
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Affiliation(s)
- Debojyoti Chakraborty
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Maciej Paszkowski-Rogacz
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Nicolas Berger
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Li Ding
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Jovan Mircetic
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Jun Fu
- Genomics, Biotechnology Center, TU Dresden, BioInnovationsZentrum, Tatzberg 47, 01307 Dresden, Germany
| | - Vytautas Iesmantavicius
- The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Chunaram Choudhary
- The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
| | - Konstantinos Anastassiadis
- Stem Cell Engineering, Biotechnology Center, TU Dresden, BioInnovationsZentrum, Tatzberg 47, 01307 Dresden, Germany
| | - A Francis Stewart
- Genomics, Biotechnology Center, TU Dresden, BioInnovationsZentrum, Tatzberg 47, 01307 Dresden, Germany
| | - Frank Buchholz
- Medical Systems Biology, UCC, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Dresden, 01307 Dresden, Germany; National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
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16
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Winzi M, Casas Vila N, Paszkowski-Rogacz M, Ding L, Noack S, Theis M, Butter F, Buchholz F. The long noncoding RNA lncR492 inhibits neural differentiation of murine embryonic stem cells. PLoS One 2018; 13:e0191682. [PMID: 29364956 PMCID: PMC5783419 DOI: 10.1371/journal.pone.0191682] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 01/09/2018] [Indexed: 12/17/2022] Open
Abstract
RNA interference (RNAi) screens have been shown to be valuable to study embryonic stem cell (ESC) self-renewal and they have been successfully applied to identify coding as well as noncoding genes required for maintaining pluripotency. Here, we used an RNAi library targeting >640 long noncoding RNAs (lncRNA) to probe for their role in early cell differentiation. Utilizing a Sox1-GFP ESC reporter cell line, we identified the lncRNA lncR492 as lineage-specific inhibitor of neuroectodermal differentiation. Molecular characterization showed that lncR492 interacts with the mRNA binding protein HuR and facilitates its inhibitory function by activation of Wnt signaling. Thus, lncRNAs modulate the fate decision of pluripotent stem cells.
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Affiliation(s)
- Maria Winzi
- Medical Systems Biology, Faculty of Medicine Carl Gustav Carus, University Cancer Center, TU Dresden, Dresden, Germany
| | - Nuria Casas Vila
- Quantitative Proteomics, Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany
| | - Maciej Paszkowski-Rogacz
- Medical Systems Biology, Faculty of Medicine Carl Gustav Carus, University Cancer Center, TU Dresden, Dresden, Germany
| | - Li Ding
- Medical Systems Biology, Faculty of Medicine Carl Gustav Carus, University Cancer Center, TU Dresden, Dresden, Germany
| | - Svenja Noack
- Medical Systems Biology, Faculty of Medicine Carl Gustav Carus, University Cancer Center, TU Dresden, Dresden, Germany
| | - Mirko Theis
- Medical Systems Biology, Faculty of Medicine Carl Gustav Carus, University Cancer Center, TU Dresden, Dresden, Germany
| | - Falk Butter
- Quantitative Proteomics, Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany
| | - Frank Buchholz
- Medical Systems Biology, Faculty of Medicine Carl Gustav Carus, University Cancer Center, TU Dresden, Dresden, Germany
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
- * E-mail:
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17
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18
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Deb A, Sarkar A, Ghosh Z. Dissecting the variation in transcriptional circuits between naive and primed pluripotent states. FEBS Lett 2017. [DOI: 10.1002/1873-3468.12732] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Aritra Deb
- Bioinformatics Centre; Bose Institute; Kolkata India
| | | | - Zhumur Ghosh
- Bioinformatics Centre; Bose Institute; Kolkata India
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19
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Quan Z, Zheng D, Qing H. Regulatory Roles of Long Non-Coding RNAs in the Central Nervous System and Associated Neurodegenerative Diseases. Front Cell Neurosci 2017; 11:175. [PMID: 28713244 PMCID: PMC5491930 DOI: 10.3389/fncel.2017.00175] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 06/09/2017] [Indexed: 12/12/2022] Open
Abstract
Accumulating studies have revealed that the human genome encodes tens of thousands of long non-coding RNAs (lncRNAs), which participate in multiple biological networks modulating gene expression via transcriptional, post-transcriptional and epigenetic regulation. Strikingly, a large fraction of tissue-specific lncRNAs are expressed in the Central Nervous System (CNS) with precisely regulated temporal and spatial expression patterns. These brain-specific lncRNAs are also featured with the cell-type specificity, the highest signals of evolutionary conservation, and their preferential location adjacent to brain-expressed protein-coding genes. Mounting evidence has indicated dysregulation or mutations in lncRNA gene loci are associated with a variety of CNS-associated neurodegenerative disorders, such as Alzheimer's, Parkinson's, Huntington's diseases, Amyotrophic Lateral Sclerosis and others. However, how lncRNAs contribute to these disorders remains to be further explored and studied. In this review article, we systematically and comprehensively summarize the current studies of lncRNAs, demonstrate the specificity of lncRNAs expressed in the brain, their functions during neural development and expression profiles in major cell types of the CNS, highlight the regulatory mechanisms of several studied lncRNAs that may play essential roles in the pathophysiology of neurodegenerative diseases, and discuss the current challenges and future perspectives of lncRNA studies involved in neurodegenerative and other diseases.
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Affiliation(s)
- Zhenzhen Quan
- School of Life Science, Beijing Institute of TechnologyBeijing, China
| | - Da Zheng
- School of Life Science, Beijing Institute of TechnologyBeijing, China
| | - Hong Qing
- School of Life Science, Beijing Institute of TechnologyBeijing, China
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20
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Abstract
Background Mammary glands of dairy cattle produce milk for the newborn offspring and for human consumption. Long intergenic noncoding RNAs (lincRNAs) play various functions in eukaryotic cells. However, types and roles of lincRNAs in bovine mammary glands are still poorly understood. Results Using computational methods, 886 unknown intergenic transcripts (UITs) were identified from five RNA-seq datasets from bovine mammary glands. Their non-coding potentials were predicted by using the combination of four software programs (CPAT, CNCI, CPC and hmmscan), with 184 lincRNAs identified. By comparison to the NONCODE2016 database and a domestic-animal long noncoding RNA database (ALDB), 112 novel lincRNAs were revealed in bovine mammary glands. Many lincRNAs were found to be located in quantitative trait loci (QTL). In particular, 36 lincRNAs were found in 172 milk related QTLs, whereas one lincRNA was within clinical mastitis QTL region. In addition, targeted genes for 10 lincRNAs with the highest fragments per kilobase of transcript per million fragments mapped (FPKM) were predicted by LncTar for forecasting potential biological functions of these lincRNAs. Further analyses indicate involvement of lincRNAs in several biological functions and different pathways. Conclusion Our study has provided a panoramic view of lincRNAs in bovine mammary glands and suggested their involvement in many biological functions including susceptibility to clinical mastitis as well as milk quality and production. This integrative annotation of mammary gland lincRNAs broadens and deepens our understanding of bovine mammary gland biology. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3858-4) contains supplementary material, which is available to authorized users.
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21
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Salehi S, Taheri MN, Azarpira N, Zare A, Behzad-Behbahani A. State of the art technologies to explore long non-coding RNAs in cancer. J Cell Mol Med 2017. [PMID: 28631377 PMCID: PMC5706582 DOI: 10.1111/jcmm.13238] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Long non‐coding RNAs (lncRNAs) comprise a vast repertoire of RNAs playing a wide variety of crucial roles in tissue physiology in a cell‐specific manner. Despite being engaged in myriads of regulatory mechanisms, many lncRNAs have still remained to be assigned any functions. A constellation of experimental techniques including single‐molecule RNA in situ hybridization (sm‐RNA FISH), cross‐linking and immunoprecipitation (CLIP), RNA interference (RNAi), Clustered regularly interspaced short palindromic repeats (CRISPR) and so forth has been employed to shed light on lncRNA cellular localization, structure, interaction networks and functions. Here, we review these and other experimental approaches in common use for identification and characterization of lncRNAs, particularly those involved in different types of cancer, with focus on merits and demerits of each technique.
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Affiliation(s)
- Saeede Salehi
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Medical Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Naser Taheri
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Medical Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolhossein Zare
- Transplant Research Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abbas Behzad-Behbahani
- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Medical Biotechnology, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
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22
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Long Noncoding RNAs in Pluripotency of Stem Cells and Cell Fate Specification. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1008:223-252. [DOI: 10.1007/978-981-10-5203-3_8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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23
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Nötzold L, Frank L, Gandhi M, Polycarpou-Schwarz M, Groß M, Gunkel M, Beil N, Erfle H, Harder N, Rohr K, Trendel J, Krijgsveld J, Longerich T, Schirmacher P, Boutros M, Erhardt S, Diederichs S. The long non-coding RNA LINC00152 is essential for cell cycle progression through mitosis in HeLa cells. Sci Rep 2017; 7:2265. [PMID: 28536419 PMCID: PMC5442156 DOI: 10.1038/s41598-017-02357-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/10/2017] [Indexed: 12/28/2022] Open
Abstract
In recent years, long non-coding RNA (lncRNA) research has identified essential roles of these transcripts in virtually all physiological cellular processes including tumorigenesis, but their functions and molecular mechanisms are poorly understood. In this study, we performed a high-throughput siRNA screen targeting 638 lncRNAs deregulated in cancer entities to analyse their impact on cell division by using time-lapse microscopy. We identified 26 lncRNAs affecting cell morphology and cell cycle including LINC00152. This transcript was ubiquitously expressed in many human cell lines and its RNA levels were significantly upregulated in lung, liver and breast cancer tissues. A comprehensive sequence analysis of LINC00152 revealed a highly similar paralog annotated as MIR4435-2HG and several splice variants of both transcripts. The shortest and most abundant isoform preferentially localized to the cytoplasm. Cells depleted of LINC00152 arrested in prometaphase of mitosis and showed reduced cell viability. In RNA affinity purification (RAP) studies, LINC00152 interacted with a network of proteins that were associated with M phase of the cell cycle. In summary, we provide new insights into the properties and biological function of LINC00152 suggesting that this transcript is crucial for cell cycle progression through mitosis and thus, could act as a non-coding oncogene.
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Affiliation(s)
- Linda Nötzold
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance and CellNetworks Excellence Cluster, Heidelberg University, 69120, Heidelberg, Germany.,Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), Heidelberg University, 69129, Heidelberg, Germany
| | - Lukas Frank
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Minakshi Gandhi
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Maria Polycarpou-Schwarz
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Matthias Groß
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Manuel Gunkel
- ViroQuant-CellNetworks RNAi Screening Facility, BioQuant Center, Heidelberg University, 69120, Heidelberg, Germany
| | - Nina Beil
- ViroQuant-CellNetworks RNAi Screening Facility, BioQuant Center, Heidelberg University, 69120, Heidelberg, Germany
| | - Holger Erfle
- ViroQuant-CellNetworks RNAi Screening Facility, BioQuant Center, Heidelberg University, 69120, Heidelberg, Germany
| | - Nathalie Harder
- Department of Bioinformatics and Functional Genomics, Biomedical Computer Vision Group, Heidelberg University, BioQuant, IPMB, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.,Definiens AG, 80636, Munich, Germany
| | - Karl Rohr
- Department of Bioinformatics and Functional Genomics, Biomedical Computer Vision Group, Heidelberg University, BioQuant, IPMB, and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Jakob Trendel
- German Cancer Research Center (DKFZ), Excellence Cluster CellNetworks, Heidelberg University, 69120, Heidelberg, Germany.,European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117, Heidelberg, Germany
| | - Jeroen Krijgsveld
- German Cancer Research Center (DKFZ), Excellence Cluster CellNetworks, Heidelberg University, 69120, Heidelberg, Germany.,European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117, Heidelberg, Germany
| | - Thomas Longerich
- Institute of Pathology University Hospital RWTH Aachen, 52074, Aachen, Germany.,Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Michael Boutros
- Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ) and Department of Cell and Molecular Biology, Medical Faculty Mannheim, Heidelberg University, 69120, Heidelberg, Germany
| | - Sylvia Erhardt
- Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance and CellNetworks Excellence Cluster, Heidelberg University, 69120, Heidelberg, Germany.,Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), Heidelberg University, 69129, Heidelberg, Germany
| | - Sven Diederichs
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. .,Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), Heidelberg University, 69129, Heidelberg, Germany. .,Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany. .,Division of Cancer Research, Dept. of Thoracic Surgery, Medical Center - University of Freiburg, 79106, Freiburg, Germany. .,Faculty of Medicine, University of Freiburg, 79085, Freiburg, Germany. .,German Cancer Consortium (DKTK), 79104, Freiburg, Germany.
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Seiler J, Breinig M, Caudron-Herger M, Polycarpou-Schwarz M, Boutros M, Diederichs S. The lncRNA VELUCT strongly regulates viability of lung cancer cells despite its extremely low abundance. Nucleic Acids Res 2017; 45:5458-5469. [PMID: 28160600 PMCID: PMC5435915 DOI: 10.1093/nar/gkx076] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/24/2017] [Accepted: 01/26/2017] [Indexed: 01/22/2023] Open
Abstract
Little is known about the function of most non-coding RNAs (ncRNAs). The majority of long ncRNAs (lncRNAs) is expressed at very low levels and it is a matter of intense debate whether these can be of functional relevance. Here, we identified lncRNAs regulating the viability of lung cancer cells in a high-throughput RNA interference screen. Based on our previous expression profiling, we designed an siRNA library targeting 638 lncRNAs upregulated in human cancer. In a functional siRNA screen analyzing the viability of lung cancer cells, the most prominent hit was a novel lncRNA which we called Viability Enhancing LUng Cancer Transcript (VELUCT). In silico analyses confirmed the non-coding properties of the transcript. Surprisingly, VELUCT was below the detection limit in total RNA from NCI-H460 cells by RT-qPCR as well as RNA-Seq, but was robustly detected in the chromatin-associated RNA fraction. It is an extremely low abundant lncRNA with an RNA copy number of less than one copy per cell. Blocking transcription with actinomycin D revealed that VELUCT RNA was highly unstable which may partially explain its low steady-state concentration. Despite its extremely low abundance, loss-of-function of VELUCT with three independent experimental approaches in three different lung cancer cell lines led to a significant reduction of cell viability: Next to four individual siRNAs, also two complex siPOOLs as well as two antisense oligonucleotides confirmed the strong and specific phenotype. In summary, the extremely low abundant lncRNA VELUCT is essential for regulation of cell viability in several lung cancer cell lines. Hence, VELUCT is the first example for a lncRNA that is expressed at a very low level, but has a strong loss-of-function phenotype. Thus, our study proves that at least individual low-abundant lncRNAs can play an important functional role.
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Affiliation(s)
- Jana Seiler
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marco Breinig
- Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Maïwen Caudron-Herger
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Michael Boutros
- Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sven Diederichs
- Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Cancer Research, Dept. of Thoracic Surgery, Medical Center – University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Freiburg, Germany
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25
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Luginbühl J, Sivaraman DM, Shin JW. The essentiality of non-coding RNAs in cell reprogramming. Noncoding RNA Res 2017; 2:74-82. [PMID: 30159423 PMCID: PMC6096403 DOI: 10.1016/j.ncrna.2017.04.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 04/03/2017] [Accepted: 04/11/2017] [Indexed: 02/07/2023] Open
Abstract
In mammals, short (mi-) and long non-coding (lnc) RNAs are immensely abundant and they are proving to be more functional than ever before. Particularly in cell reprogramming, non-coding RNAs are essential to establish the pluripotent network and are indispensable to reprogram somatic cells to pluripotency. Through systematic screening and mechanistic studies, diverse functional features of both miRNA and lncRNAs have emerged as either scaffolds, inhibitors, or co-activators, necessary to orchestrate the intricacy of gene regulation. Furthermore, the collective characterizations of both miRNA and lncRNA reveal their interdependency (e.g. sequestering the function of the other) to modulate cell reprogramming. This review broadly explores the regulatory processes of cell reprogramming - with key functional examples in neuronal and cardiac differentiations - in the context of both short and long non-coding RNAs.
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Affiliation(s)
| | | | - Jay W. Shin
- RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa, 230-0045 Japan
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26
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Signal B, Gloss BS, Dinger ME. Computational Approaches for Functional Prediction and Characterisation of Long Noncoding RNAs. Trends Genet 2016; 32:620-637. [PMID: 27592414 DOI: 10.1016/j.tig.2016.08.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 08/03/2016] [Accepted: 08/04/2016] [Indexed: 02/09/2023]
Abstract
Although a considerable portion of eukaryotic genomes is transcribed as long noncoding RNAs (lncRNAs), the vast majority are functionally uncharacterised. The rapidly expanding catalogue of mechanistically investigated lncRNAs has provided evidence for distinct functional subclasses, which are now ripe for exploitation as a general model to predict functions for uncharacterised lncRNAs. By utilising publicly-available genome-wide datasets and computational methods, we present several developed and emerging in silico approaches to characterise and predict the functions of lncRNAs. We propose that the application of these techniques provides valuable functional and mechanistic insight into lncRNAs, and is a crucial step for informing subsequent functional studies.
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Affiliation(s)
- Bethany Signal
- Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - Brian S Gloss
- Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - Marcel E Dinger
- Garvan Institute of Medical Research, Sydney, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
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27
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Nguyen Q, Carninci P. Expression Specificity of Disease-Associated lncRNAs: Toward Personalized Medicine. Curr Top Microbiol Immunol 2016; 394:237-58. [PMID: 26318140 DOI: 10.1007/82_2015_464] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Long noncoding RNAs (lncRNAs) perform diverse regulatory functions in transcription, translation' chromatin modification, and cellular organization. Misregulation of lncRNAs is found linked to various human diseases. Compared to protein-coding RNAs' lncRNAs are more specific to organs, tissues, cell types, developmental stages, and disease conditions' making them promising candidates as diagnostic and prognostic biomarkers and as gene therapy targets. The functional annotation of mammalian genome (FANTOM) consortium utilizes cap analysis of gene expression (CAGE) method to quantify genome-wide activities of promoters and enhancers of coding and noncoding RNAs across a large collection of human and mouse tissues' cell types' diseases, and time-courses. The project discovered widespread transcription of major lncRNA classes, including lncRNAs derived from enhancers' bidirectional promoters' antisense lncRNAs' and repetitive elements. Results from FANTOM project enable assessment of lncRNA expression specificity across tissue and disease conditions' based on differential promoter and enhancer usage. More than 85 % of disease-related SNPs are within noncoding regions and are strikingly overrepresented in enhancer and promoter regions, suggestive of the importance of lncRNA loci at these SNP harboring regions to human diseases. In this chapter' we discuss lncRNA expression specificity' review diverse functions of disease-associated lncRNAs' and present perspectives on their potential therapeutic applications for personalized medicine. The future development of lncRNA applications relies on technologies to identify and validate their functions' structures' and mechanisms. Comprehensive understanding of genome-wide interaction networks of lncRNAs with proteins, chromatins, and other RNAs in regulating cellular processes will allow personalized medicine to use lncRNAs as highly specific biomarkers in diagnosis' prognosis, and therapeutic targets.
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Affiliation(s)
- Quan Nguyen
- Division of Genomic Technologies, RIKEN Yokohama Campus, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-Cho, Tsurumi-Ku, Yokohama City, Kanagawa, 230-0045, Japan
| | - Piero Carninci
- Division of Genomic Technologies, RIKEN Yokohama Campus, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-Cho, Tsurumi-Ku, Yokohama City, Kanagawa, 230-0045, Japan.
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28
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Qin D, Xu C. Study strategies for long non-coding RNAs and their roles in regulating gene expression. Cell Mol Biol Lett 2016. [PMID: 26204411 DOI: 10.1515/cmble-2015-0021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) have attracted considerable attention recently due to their involvement in numerous key cellular processes and in the development of various disorders. New high-throughput methods enable their study on a genome-wide scale. Numerous lncRNAs have been identified and characterized as important members of the biological regulatory network, with significant roles in regulating gene expression at the epigenetic, transcriptional and post-transcriptional levels. This paper summarizes the diverse mechanisms of action of these lncRNAs and looks at the study strategies in this field. A major challenge in future study is to establish more effective bioinformatics and experimental methods to explore the functions, detailed mechanisms of action and structures deciding the functional diversity of lncRNAs, since the vast majority remain unresolved.
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29
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Aprea J, Calegari F. Long non-coding RNAs in corticogenesis: deciphering the non-coding code of the brain. EMBO J 2015; 34:2865-84. [PMID: 26516210 DOI: 10.15252/embj.201592655] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 10/05/2015] [Indexed: 01/17/2023] Open
Abstract
Evidence on the role of long non-coding (lnc) RNAs has been accumulating over decades, but it has been only recently that advances in sequencing technologies have allowed the field to fully appreciate their abundance and diversity. Despite this, only a handful of lncRNAs have been phenotypically or mechanistically studied. Moreover, novel lncRNAs and new classes of RNAs are being discovered at growing pace, suggesting that this class of molecules may have functions as diverse as protein-coding genes. Interestingly, the brain is the organ where lncRNAs have the most peculiar features including the highest number of lncRNAs that are expressed, proportion of tissue-specific lncRNAs and highest signals of evolutionary conservation. In this work, we critically review the current knowledge about the steps that have led to the identification of the non-coding transcriptome including the general features of lncRNAs in different contexts in terms of both their genomic organisation, evolutionary origin, patterns of expression, and function in the developing and adult mammalian brain.
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Affiliation(s)
- Julieta Aprea
- DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Federico Calegari
- DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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30
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Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells 2015; 7:1150-1184. [PMID: 26516408 PMCID: PMC4620423 DOI: 10.4252/wjsc.v7.i9.1150] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/30/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
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31
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Oral Presentations. Regen Med 2015. [DOI: 10.2217/rme.15.72] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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32
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Jiang HY, Zou J, Yu XF. Expression and regulation of long non-coding RNAs in colorectal cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:3567-3575. [DOI: 10.11569/wcjd.v23.i22.3567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNA (lncRNA) has a messenger RNA-like structure, greater than 200 nucleotides in length, and extensively existing in both the cytoplasm and nucleus. However, almost all lncRNAs cannot be transcribed into proteins. Increasing studies showed that lncRNAs participate in many eukaryotic activities, such as regulating the expression of genes at epigenetic, transcriptional and post-transcriptional levels, and regulating human growth and development, and also, cell apoptosis. Their aberrant expression is involved in many human diseases and tumorigenesis. This article reviews the latest results of lncRNAs in colorectal cancer with regards to their expression and regulation.
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33
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Targeting Human Long Noncoding Transcripts by Endoribonuclease-Prepared siRNAs. ACTA ACUST UNITED AC 2015; 20:1018-26. [DOI: 10.1177/1087057115583448] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 03/24/2015] [Indexed: 11/15/2022]
Abstract
Broad sequencing enterprises such as the FANTOM or ENCODE projects have substantially extended our knowledge of the human transcriptome. They have revealed that a large portion of genomic DNA is actively transcribed and have identified a plethora of novel transcripts. Many newly identified transcripts belong to the class of long noncoding RNAs (lncRNAs), which range from a few hundred bases to multiple kilobases in length and harbor no protein-coding potential. Although the biological activity of some lncRNAs is understood, the functions of most lncRNAs remain elusive. Tools that allow rapid and cost-effective access to functional data of lncRNAs are therefore essential. Here, we describe the construction and validation of an endoribonuclease-prepared siRNA (esiRNA) library designed to target 1779 individual human lncRNAs by RNA interference. We present a compendium of lncRNA expression data for 11 human cancer cell lines. Furthermore, we show that the resource is suitable for combined knockdown and localization analysis. We discuss challenges in sequence annotation of lncRNAs with respect to their often low and cell type–specific expression and specify esiRNAs that are suitable for targeting lncRNAs in commonly used human cell lines.
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34
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Ding J, Eyre S, Worthington J. Genetics of RA susceptibility, what comes next? RMD Open 2015; 1:e000028. [PMID: 26509058 PMCID: PMC4612696 DOI: 10.1136/rmdopen-2014-000028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/25/2015] [Accepted: 03/28/2015] [Indexed: 02/01/2023] Open
Abstract
Genome-wide association studies (GWASs) have been used to great effect to identify genetic susceptibility loci for complex disease. A series of GWAS and meta-analyses have informed the discovery of over 100 loci for rheumatoid arthritis (RA). In common with findings in other autoimmune diseases the lead signals for the majority of these loci do not map to known gene sequences. In order to realise the benefit of investment in GWAS studies it is vital we determine how disease associated alleles function to influence disease processes. This is leading to rapid development in our knowledge as to the function of non-coding regions of the genome. Here we consider possible functional mechanisms for intergenic RA-associated variants which lie within lncRNA sequences.
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Affiliation(s)
- James Ding
- Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester , Manchester , UK
| | - Stephen Eyre
- Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester , Manchester , UK
| | - Jane Worthington
- Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester , Manchester , UK
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35
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Predicting the functions of long noncoding RNAs using RNA-seq based on Bayesian network. BIOMED RESEARCH INTERNATIONAL 2015; 2015:839590. [PMID: 25815337 PMCID: PMC4359839 DOI: 10.1155/2015/839590] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Revised: 02/05/2015] [Accepted: 02/06/2015] [Indexed: 02/01/2023]
Abstract
Long noncoding RNAs (lncRNAs) have been shown to play key roles in various biological processes. However, functions of most lncRNAs are poorly characterized. Here, we represent a framework to predict functions of lncRNAs through construction of a regulatory network between lncRNAs and protein-coding genes. Using RNA-seq data, the transcript profiles of lncRNAs and protein-coding genes are constructed. Using the Bayesian network method, a regulatory network, which implies dependency relations between lncRNAs and protein-coding genes, was built. In combining protein interaction network, highly connected coding genes linked by a given lncRNA were subsequently used to predict functions of the lncRNA through functional enrichment. Application of our method to prostate RNA-seq data showed that 762 lncRNAs in the constructed regulatory network were assigned functions. We found that lncRNAs are involved in diverse biological processes, such as tissue development or embryo development (e.g., nervous system development and mesoderm development). By comparison with functions inferred using the neighboring gene-based method and functions determined using lncRNA knockdown experiments, our method can provide comparable predicted functions of lncRNAs. Overall, our method can be applied to emerging RNA-seq data, which will help researchers identify complex relations between lncRNAs and coding genes and reveal important functions of lncRNAs.
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36
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Bassett AR, Akhtar A, Barlow DP, Bird AP, Brockdorff N, Duboule D, Ephrussi A, Ferguson-Smith AC, Gingeras TR, Haerty W, Higgs DR, Miska EA, Ponting CP. Considerations when investigating lncRNA function in vivo. eLife 2014; 3:e03058. [PMID: 25124674 PMCID: PMC4132285 DOI: 10.7554/elife.03058] [Citation(s) in RCA: 278] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Although a small number of the vast array of animal long non-coding RNAs (lncRNAs) have known effects on cellular processes examined in vitro, the extent of their contributions to normal cell processes throughout development, differentiation and disease for the most part remains less clear. Phenotypes arising from deletion of an entire genomic locus cannot be unequivocally attributed either to the loss of the lncRNA per se or to the associated loss of other overlapping DNA regulatory elements. The distinction between cis- or trans-effects is also often problematic. We discuss the advantages and challenges associated with the current techniques for studying the in vivo function of lncRNAs in the light of different models of lncRNA molecular mechanism, and reflect on the design of experiments to mutate lncRNA loci. These considerations should assist in the further investigation of these transcriptional products of the genome. DOI:http://dx.doi.org/10.7554/eLife.03058.001
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Affiliation(s)
- Andrew R Bassett
- Andrew R Bassett is in the MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
| | - Asifa Akhtar
- Asifa Akhtar is in the Department of Chromatin Regulation, Max-Planck-Institut für Immunbiologie und Epigenetik, Freiburg im Breisgau, Germany
| | - Denise P Barlow
- Denise P Barlow is in the CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Adrian P Bird
- Adrian P Bird is in the Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom
| | - Neil Brockdorff
- Neil Brockdorff is in the Department of Biochemistry, University of Oxford, Oxford, United Kingdom
| | - Denis Duboule
- Denis Duboule is in the School of Life Sciences, Ecole Polytechnique Fédérale Lausanne, Lausanne, Switzerland; Department of Genetics and Evolution, Université de Genève, Geneva, Switzerland
| | - Anne Ephrussi
- Anne Ephrussi is in the Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Anne C Ferguson-Smith
- Anne C Ferguson-Smith is in the Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Thomas R Gingeras
- Thomas R Gingeras is in the Functional Genomics Group, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
| | - Wilfried Haerty
- Wilfried Haerty is in the MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Douglas R Higgs
- Douglas R Higgs is in the MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom
| | - Eric A Miska
- Eric A Miska is in the Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom; Department of Genetics, University of Cambridge, Cambridge, United Kingdom
| | - Chris P Ponting
- Chris P Ponting is in the MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; Wellcome Trust Sanger Institute, Cambridge, United Kingdom
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37
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Bai Y, Dai X, Harrison AP, Chen M. RNA regulatory networks in animals and plants: a long noncoding RNA perspective. Brief Funct Genomics 2014; 14:91-101. [PMID: 24914100 DOI: 10.1093/bfgp/elu017] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
A recent highlight of genomics research has been the discovery of many families of transcripts which have function but do not code for proteins. An important group is long noncoding RNAs (lncRNAs), which are typically longer than 200 nt, and whose members originate from thousands of loci across genomes. We review progress in understanding the biogenesis and regulatory mechanisms of lncRNAs. We describe diverse computational and high throughput technologies for identifying and studying lncRNAs. We discuss the current knowledge of functional elements embedded in lncRNAs as well as insights into the lncRNA-based regulatory network in animals. We also describe genome-wide studies of large amount of lncRNAs in plants, as well as knowledge of selected plant lncRNAs with a focus on biotic/abiotic stress-responsive lncRNAs.
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38
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Alvarez-Dominguez JR, Hu W, Gromatzky AA, Lodish HF. Long noncoding RNAs during normal and malignant hematopoiesis. Int J Hematol 2014; 99:531-41. [PMID: 24609766 DOI: 10.1007/s12185-014-1552-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/25/2014] [Accepted: 02/18/2014] [Indexed: 11/28/2022]
Abstract
Long noncoding RNAs (lncRNAs) are increasingly recognized to contribute to cellular development via diverse mechanisms during both health and disease. Here, we highlight recent progress on the study of lncRNAs that function in the development of blood cells. We emphasize lncRNAs that regulate blood cell fates through epigenetic control of gene expression, an emerging theme among functional lncRNAs. Many of these noncoding genes and their targets become dysregulated during malignant hematopoiesis, directly implicating lncRNAs in blood cancers such as leukemia. In a few cases, dysregulation of an lncRNA alone leads to malignant hematopoiesis in a mouse model. Thus, lncRNAs may be not only useful as markers for the diagnosis and prognosis of cancers of the blood, but also as potential targets for novel therapies.
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39
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Bai W, Yang J, Yang G, Niu P, Tian L, Gao A. Long non-coding RNA NR_045623 and NR_028291 involved in benzene hematotoxicity in occupationally benzene-exposed workers. Exp Mol Pathol 2014; 96:354-60. [PMID: 24613687 DOI: 10.1016/j.yexmp.2014.02.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 02/28/2014] [Indexed: 01/08/2023]
Abstract
Benzene is an established human hematotoxicant and leukemogen. New insights into the pathogenesis of benzene hematotoxicity are urgently needed. Long non-coding RNA (lncRNA) widely participate in various physiological and pathological processes. It has been shown that lncRNA plays an important role in hematologic malignancy tumorigenesis. However, the expression and biological function of lncRNA during benzene hematotoxicity progress remain largely unknown. An integrated analysis of differentially expressed lncRNA and mRNA was performed to identify genes which were likely to be critical for benzene hematotoxicity through Microarray analysis. Dynamic gene network analysis of the differentially expressed lncRNA and mRNA was constructed and two main lncRNA (NR_045623 and NR_028291) were discovered and two key lncRNA subnets were involved in immune responses, hematopoiesis, B cell receptor signaling pathway and chronic myeloid leukemia. These findings suggested that NR_045623 and NR_028291 might be the key genes associated with benzene hematotoxicity.
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Affiliation(s)
- Wenlin Bai
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Jing Yang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Gengxia Yang
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Piye Niu
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Lin Tian
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China
| | - Ai Gao
- Department of Occupational Health and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing 100069, China.
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40
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Yang YW, Flynn RA, Chen Y, Qu K, Wan B, Wang KC, Lei M, Chang HY. Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency. eLife 2014; 3:e02046. [PMID: 24521543 PMCID: PMC3921674 DOI: 10.7554/elife.02046] [Citation(s) in RCA: 158] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The WDR5 subunit of the MLL complex enforces active chromatin and can bind RNA; the relationship between these two activities is unclear. Here we identify a RNA binding pocket on WDR5, and discover a WDR5 mutant (F266A) that selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. Complementation in ESCs shows that WDR5 F266A mutant is unable to accumulate on chromatin, and is defective in gene activation, maintenance of histone H3 lysine 4 trimethylation, and ESC self renewal. We identify a family of ESC messenger and lncRNAs that interact with wild type WDR5 but not F266A mutant, including several lncRNAs known to be important for ESC gene expression. These results suggest that specific RNAs are integral inputs into the WDR5-MLL complex for maintenance of the active chromatin state and embryonic stem cell fates. DOI: http://dx.doi.org/10.7554/eLife.02046.001.
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Affiliation(s)
- Yul W Yang
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, United States
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41
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Zhu J, Fu H, Wu Y, Zheng X. Function of lncRNAs and approaches to lncRNA-protein interactions. SCIENCE CHINA-LIFE SCIENCES 2013; 56:876-85. [PMID: 24091684 DOI: 10.1007/s11427-013-4553-6] [Citation(s) in RCA: 269] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 09/05/2013] [Indexed: 01/10/2023]
Abstract
Long non-coding RNAs (lncRNAs), which represent a new frontier in molecular biology, play important roles in regulating gene expression at epigenetic, transcriptional and post-transcriptional levels. More and more lncRNAs have been found to play important roles in normal cell physiological activities, and participate in the development of varieties of tumors and other diseases. Previously, we have only been able to determine the function of lncRNAs through multiple mechanisms, including genetic imprinting, chromatin remodeling, splicing regulation, mRNA decay, and translational regulation. Application of technological advances to research into the function of lncRNAs is extremely important. The major tools for exploring lncRNAs include microarrays, RNA sequencing (RNA-seq), Northern blotting, real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH), RNA interference (RNAi), RNA-binding protein immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), crosslinking-immunopurification (CLIP), and bioinformatic prediction. In this review, we highlight the functions of lncRNAs, and advanced methods to research lncRNA-protein interactions.
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Affiliation(s)
- Juanjuan Zhu
- Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing, 100850, China
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Jia W, Chen W, Kang J. The functions of microRNAs and long non-coding RNAs in embryonic and induced pluripotent stem cells. GENOMICS PROTEOMICS & BIOINFORMATICS 2013; 11:275-83. [PMID: 24096129 PMCID: PMC4357836 DOI: 10.1016/j.gpb.2013.09.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 09/02/2013] [Accepted: 09/03/2013] [Indexed: 12/19/2022]
Abstract
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) hold immense promise for regenerative medicine due to their abilities to self-renew and to differentiate into all cell types. This unique property is controlled by a complex interplay between transcriptional factors and epigenetic regulators. Recent research indicates that the epigenetic role of non-coding RNAs (ncRNAs) is an integral component of this regulatory network. This report will summarize findings that focus on two classes of regulatory ncRNAs, microRNAs (miRNAs) and long ncRNAs (lncRNAs), in the induction, maintenance and directed differentiation of ESCs and iPSCs. Manipulating these two important types of ncRNAs would be crucial to unlock the therapeutic and research potential of pluripotent stem cells.
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Affiliation(s)
- Wenwen Jia
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China
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43
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Mustafi D, Kevany BM, Bai X, Maeda T, Sears JE, Khalil AM, Palczewski K. Evolutionarily conserved long intergenic non-coding RNAs in the eye. Hum Mol Genet 2013; 22:2992-3002. [PMID: 23562822 PMCID: PMC3699063 DOI: 10.1093/hmg/ddt156] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 04/02/2013] [Indexed: 02/01/2023] Open
Abstract
The discovery that the mammalian transcriptome encodes thousands of long intergenic non-coding (linc) RNA transcripts, together with recent evidence that lincRNAs can regulate protein-coding genes, has added a new level of complexity to cellular transcriptional/translational regulation. Indeed several reports now link mutations in lincRNAs to heritable human disorders. Here, we identified a subset of lincRNAs in terminally differentiated adult human retinal neurons based on their sequence conservation across species. RNA sequencing of eye tissue from several mammalian species with varied rod/cone photoreceptor content identified 18 lincRNAs that were highly conserved across these species. Sixteen of the 18 were conserved in human retinal tissue with 14 of these also conserved in the macular region. A subset of lincRNAs exhibited restricted tissue expression profiles in mice, with preferential expression in the retina. Mouse models with different populations of retinal cells as well as in situ hybridization provided evidence that these lincRNAs localized to specific retinal compartments, most notably to the photoreceptor neuronal layer. Computational genomic loci and promoter region analyses provided a basis for regulated expression of these conserved lincRNAs in retinal post-mitotic neurons. This combined approach identified several lincRNAs that could be critical for retinal and visual maintenance in adults.
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Affiliation(s)
| | | | | | - Tadao Maeda
- Department of Ophthalmology and Visual Sciences and
| | - Jonathan E. Sears
- Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44106-4965, USA and
| | - Ahmad M. Khalil
- Center for RNA Molecular Biology
- Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4965, USA
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44
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Getting to the heart of the matter: long non-coding RNAs in cardiac development and disease. EMBO J 2013; 32:1805-16. [PMID: 23756463 PMCID: PMC3981183 DOI: 10.1038/emboj.2013.134] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 05/23/2013] [Indexed: 02/07/2023] Open
Abstract
Cardiogenesis in mammals requires exquisite control of gene expression and faulty regulation of transcriptional programs underpins congenital heart disease (CHD), the most common defect among live births. Similarly, many adult cardiac diseases involve transcriptional changes and sometimes have a developmental basis. Long non-coding RNAs (lncRNAs) are a novel class of transcripts that regulate cellular processes by controlling gene expression; however, detailed insights into their biological and mechanistic functions are only beginning to emerge. Here, we discuss recent findings suggesting that lncRNAs are important factors in regulation of mammalian cardiogenesis and in the pathogenesis of CHD as well as adult cardiac disease. We also outline potential methodological and conceptual considerations for future studies of lncRNAs in the heart and other contexts.
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Wu P, Zuo X, Deng H, Liu X, Liu L, Ji A. Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res Bull 2013; 97:69-80. [PMID: 23756188 DOI: 10.1016/j.brainresbull.2013.06.001] [Citation(s) in RCA: 289] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 05/31/2013] [Accepted: 06/01/2013] [Indexed: 12/11/2022]
Abstract
Long noncoding RNAs (lncRNAs) have been attracting immense research interest, while only a handful of lncRNAs have been characterized thoroughly. Their involvement in the fundamental cellular processes including regulate gene expression at epigenetics, transcription, and post-transcription highlighted a central role in cell homeostasis. However, lncRNAs studies are still at a relatively early stage, their definition, conservation, functions, and action mechanisms remain fairly complicated. Here, we give a systematic and comprehensive summary of the existing knowledge of lncRNAs in order to provide a better understanding of this new studying field. lncRNAs play important roles in brain development, neuron function and maintenance, and neurodegenerative diseases are becoming increasingly evident. In this review, we also highlighted recent studies related lncRNAs in central nervous system (CNS) development and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), and elucidated some specific lncRNAs which may be important for understanding the pathophysiology of neurodegenerative diseases, also have the potential as therapeutic targets.
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Affiliation(s)
- Ping Wu
- Center for Drug Research and Development, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China
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Ghosal S, Das S, Chakrabarti J. Long noncoding RNAs: new players in the molecular mechanism for maintenance and differentiation of pluripotent stem cells. Stem Cells Dev 2013; 22:2240-53. [PMID: 23528033 DOI: 10.1089/scd.2013.0014] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Maintenance of the pluripotent state or differentiation of the pluripotent state into any germ layer depends on the factors that orchestrate expression of thousands of genes through epigenetic, transcriptional, and post-transcriptional regulation. Long noncoding RNAs (lncRNAs) are implicated in the complex molecular circuitry in the developmental processes. The ENCODE project has opened up new avenues for studying these lncRNA transcripts with the availability of new datasets for lncRNA annotation and regulation. Expression studies identified hundreds of long noncoding RNAs differentially expressed in the pluripotent state, and many of these lncRNAs are found to control the pluripotency and stemness in embryonic and induced pluripotent stem cells or, in the reverse way, promote differentiation of pluripotent cells. They are generally transcriptionally activated or repressed by pluripotency-associated transcription factors and function as molecular mediators of gene expression that determine the pluripotent state of the cell. They can act as molecular scaffolds or guides for the chromatin-modifying complexes to direct them to bind into specific genomic loci to impart a repressive or activating effect on gene expression, or they can transcriptionally or post-transcriptionally regulate gene expression by diverse molecular mechanisms. This review focuses on recent findings on the regulatory role of lncRNAs in two main aspects of pluripotency, namely, self renewal and differentiation into any lineage, and elucidates the underlying molecular mechanisms that are being uncovered lately.
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Affiliation(s)
- Suman Ghosal
- Indian Association for the Cultivation of Science, Kolkata, India
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Ng SY, Stanton LW. Long non-coding RNAs in stem cell pluripotency. WILEY INTERDISCIPLINARY REVIEWS-RNA 2012; 4:121-8. [PMID: 23139157 DOI: 10.1002/wrna.1146] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pluripotency refers to the self-renewal of undifferentiated embryonic stem cells (ESCs), and is maintained by a tightly regulated gene regulatory network involving an intricate interplay between transcription factors and their genomic targets, as well as epigenetic processes that influence gene expression. Long non-coding RNAs (lncRNAs) are newly discovered members of gene regulatory networks that govern a variety of cell functions. Defined as RNA transcripts larger than 200 nucleotides, lncRNAs have little or no protein-coding capacity and have been shown to act via various mechanisms, and are important in a variety of biological functions. Recent reports have described the discovery of pluripotent lncRNAs involved in the maintenance and induction of stem cell pluripotency. Here, we discuss how lncRNAs may integrate into the pluripotency network, as well as prominent questions in this emerging field.
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Affiliation(s)
- Shi-Yan Ng
- Genome Institute of Singapore, Stem Cell and Developmental Biology Group, Singapore
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48
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Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Rep 2012; 13:971-83. [PMID: 23070366 DOI: 10.1038/embor.2012.145] [Citation(s) in RCA: 261] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Accepted: 09/12/2012] [Indexed: 12/20/2022] Open
Abstract
Differentiation of specialized cell types from stem and progenitor cells is tightly regulated at several levels, both during development and during somatic tissue homeostasis. Many long non-coding RNAs have been recognized as an additional layer of regulation in the specification of cellular identities; these non-coding species can modulate gene-expression programmes in various biological contexts through diverse mechanisms at the transcriptional, translational or messenger RNA stability levels. Here, we summarize findings that implicate long non-coding RNAs in the control of mammalian cell differentiation. We focus on several representative differentiation systems and discuss how specific long non-coding RNAs contribute to the regulation of mammalian development.
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