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1
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Le LTT. Long non coding RNA function in epigenetic memory with a particular emphasis on genomic imprinting and X chromosome inactivation. Gene 2025; 943:149290. [PMID: 39880342 DOI: 10.1016/j.gene.2025.149290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 12/13/2024] [Accepted: 01/25/2025] [Indexed: 01/31/2025]
Abstract
Cells preserve and convey certain gene expression patterns to their progeny through the mechanism called epigenetic memory. Epigenetic memory, encoded by epigenetic markers and components, determines germline inheritance, genomic imprinting, and X chromosome inactivation. First discovered long non coding RNAs were implicated in genomic imprinting and X-inactivation and these two phenomena clearly demonstrate the role of lncRNAs in epigenetic memory regulation. Undoubtedly, lncRNAs are well-suited for regulating genes in close proximity at imprinted loci. Due to prolonged association with the transcription site, lncRNAs are able to guide chromatin modifiers to certain locations, thereby enabling accurate temporal and spatial regulation. Nevertheless, the current state of knowledge regarding lncRNA biology and imprinting processes is still in its nascent phase. Herein, we provide a synopsis of recent scientific advancements to enhance our comprehension of lncRNAs and their functions in epigenetic memory, with a particular emphasis on genomic imprinting and X chromosome inactivation, thus gaining a deeper understanding of the role of lncRNAs in epigenetic regulatory networks.
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Affiliation(s)
- Linh T T Le
- Faculty of Biotechnology, Ho Chi Minh City Open University, Ho Chi Minh City 700000 Viet Nam
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2
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Krzyżewska A, Kurakula K. Sex Dimorphism in Pulmonary Arterial Hypertension Associated With Autoimmune Diseases. Arterioscler Thromb Vasc Biol 2024; 44:2169-2190. [PMID: 39145392 DOI: 10.1161/atvbaha.124.320886] [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] [Indexed: 08/16/2024]
Abstract
Pulmonary hypertension is a rare, incurable, and progressive disease. Although there is increasing evidence that immune disorders, particularly those associated with connective tissue diseases, are a strong predisposing factor in the development of pulmonary arterial hypertension (PAH), there is currently a lack of knowledge about the detailed molecular mechanisms responsible for this phenomenon. Exploring this topic is crucial because patients with an immune disorder combined with PAH have a worse prognosis and higher mortality compared with patients with other PAH subtypes. Moreover, data recorded worldwide show that the prevalence of PAH in women is 2× to even 4× higher than in men, and the ratio of PAH associated with autoimmune diseases is even higher (9:1). Sexual dimorphism in the pathogenesis of cardiovascular disease was explained for many years by the action of female sex hormones. However, there are increasing reports of interactions between sex hormones and sex chromosomes, and differences in the pathogenesis of cardiovascular disease may be controlled not only by sex hormones but also by sex chromosome pathways that are not dependent on the gonads. This review discusses the role of estrogen and genetic factors including the role of genes located on the X chromosome, as well as the potential protective role of the Y chromosome in sexual dimorphism, which is prominent in the occurrence of PAH associated with autoimmune diseases. Moreover, an overview of animal models that could potentially play a role in further investigating the aforementioned link was also reviewed.
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Affiliation(s)
- Anna Krzyżewska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Poland (A.K.)
| | - Kondababu Kurakula
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Free University Medical Center, the Netherlands (K.K.)
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3
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Koshiguchi M, Yonezawa N, Hatano Y, Suenaga H, Yamagata K, Kobayashi S. A system to analyze the initiation of random X-chromosome inactivation using time-lapse imaging of single cells. Sci Rep 2024; 14:20327. [PMID: 39223177 PMCID: PMC11369159 DOI: 10.1038/s41598-024-71105-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
In female eutherian mammal development, X-chromosome inactivation (XCI) of one of the two X chromosomes is initiated early. Understanding the relationship between the initiation of XCI and cell fate is critical for understanding early female development and requires a system that can monitor XCI in single living cells. Traditional embryonic stem cells (ESCs) used for XCI studies often lose X chromosomes spontaneously during culture and differentiation, making accurate monitoring difficult. Additionally, most XCI assessment methods necessitate cell disruption, hindering cell fate tracking. We developed the Momiji (version 2) ESC line to address these difficulties, enabling real-time monitoring of X-chromosome activity via fluorescence. We inserted green and red fluorescent reporter genes and neomycin and puromycin resistance genes into the two X chromosomes of PGK12.1 ESCs, creating a female ESC line that retains two X chromosomes more faithfully during differentiation. Momiji (version 2) ESCs exhibit a more stable XX karyotype than other ESC lines, including the parental PGK12.1 line. This new tool offers valuable insights into the relationship between XCI and cell fate, improving our understanding of early female development.
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Affiliation(s)
- Manami Koshiguchi
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koutou-ku, Tokyo, 135-0064, Japan
- RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Hyogo, 650-0047, Japan
| | - Nao Yonezawa
- Faculty of Biology-Oriented Science and Technology, Kindai University, Kinokawa, Wakayama, 649-6493, Japan
| | - Yu Hatano
- Faculty of Biology-Oriented Science and Technology, Kindai University, Kinokawa, Wakayama, 649-6493, Japan
- Faculty of Life and Environmental Science, University of Yamanashi, Kofu, Yamanashi, 400-8510, Japan
| | - Hikaru Suenaga
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koutou-ku, Tokyo, 135-0064, Japan
| | - Kazuo Yamagata
- Faculty of Biology-Oriented Science and Technology, Kindai University, Kinokawa, Wakayama, 649-6493, Japan
| | - Shin Kobayashi
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 2-4-7 Aomi, Koutou-ku, Tokyo, 135-0064, Japan.
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4
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de Castro RCF, Buranello TW, Recchia K, de Souza AF, Pieri NCG, Bressan FF. Emerging Contributions of Pluripotent Stem Cells to Reproductive Technologies in Veterinary Medicine. J Dev Biol 2024; 12:14. [PMID: 38804434 PMCID: PMC11130827 DOI: 10.3390/jdb12020014] [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: 01/28/2024] [Revised: 04/10/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024] Open
Abstract
The generation of mature gametes and competent embryos in vitro from pluripotent stem cells has been successfully achieved in a few species, mainly in mice, with recent advances in humans and scarce preliminary reports in other domestic species. These biotechnologies are very attractive as they facilitate the understanding of developmental mechanisms and stages that are generally inaccessible during early embryogenesis, thus enabling advanced reproductive technologies and contributing to the generation of animals of high genetic merit in a short period. Studies on the production of in vitro embryos in pigs and cattle are currently used as study models for humans since they present more similar characteristics when compared to rodents in both the initial embryo development and adult life. This review discusses the most relevant biotechnologies used in veterinary medicine, focusing on the generation of germ-cell-like cells in vitro through the acquisition of totipotent status and the production of embryos in vitro from pluripotent stem cells, thus highlighting the main uses of pluripotent stem cells in livestock species and reproductive medicine.
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Affiliation(s)
- Raiane Cristina Fratini de Castro
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of Sao Paulo, São Paulo 01001-010, SP, Brazil; (R.C.F.d.C.); (T.W.B.); (K.R.)
| | - Tiago William Buranello
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of Sao Paulo, São Paulo 01001-010, SP, Brazil; (R.C.F.d.C.); (T.W.B.); (K.R.)
| | - Kaiana Recchia
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of Sao Paulo, São Paulo 01001-010, SP, Brazil; (R.C.F.d.C.); (T.W.B.); (K.R.)
| | - Aline Fernanda de Souza
- Department of Veterinary Medicine, School of Animal Sciences and Food Engineering, University of Sao Paulo, Pirassununga 13635-900, SP, Brazil;
| | - Naira Caroline Godoy Pieri
- Department of Veterinary Medicine, School of Animal Sciences and Food Engineering, University of Sao Paulo, Pirassununga 13635-900, SP, Brazil;
| | - Fabiana Fernandes Bressan
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of Sao Paulo, São Paulo 01001-010, SP, Brazil; (R.C.F.d.C.); (T.W.B.); (K.R.)
- Department of Veterinary Medicine, School of Animal Sciences and Food Engineering, University of Sao Paulo, Pirassununga 13635-900, SP, Brazil;
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5
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Singh A, Rappolee DA, Ruden DM. Epigenetic Reprogramming in Mice and Humans: From Fertilization to Primordial Germ Cell Development. Cells 2023; 12:1874. [PMID: 37508536 PMCID: PMC10377882 DOI: 10.3390/cells12141874] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/10/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
In this review, advances in the understanding of epigenetic reprogramming from fertilization to the development of primordial germline cells in a mouse and human embryo are discussed. To gain insights into the molecular underpinnings of various diseases, it is essential to comprehend the intricate interplay between genetic, epigenetic, and environmental factors during cellular reprogramming and embryonic differentiation. An increasing range of diseases, including cancer and developmental disorders, have been linked to alterations in DNA methylation and histone modifications. Global epigenetic reprogramming occurs in mammals at two stages: post-fertilization and during the development of primordial germ cells (PGC). Epigenetic reprogramming after fertilization involves rapid demethylation of the paternal genome mediated through active and passive DNA demethylation, and gradual demethylation in the maternal genome through passive DNA demethylation. The de novo DNA methyltransferase enzymes, Dnmt3a and Dnmt3b, restore DNA methylation beginning from the blastocyst stage until the formation of the gastrula, and DNA maintenance methyltransferase, Dnmt1, maintains methylation in the somatic cells. The PGC undergo a second round of global demethylation after allocation during the formative pluripotent stage before gastrulation, where the imprints and the methylation marks on the transposable elements known as retrotransposons, including long interspersed nuclear elements (LINE-1) and intracisternal A-particle (IAP) elements are demethylated as well. Finally, DNA methylation is restored in the PGC at the implantation stage including sex-specific imprints corresponding to the sex of the embryo. This review introduces a novel perspective by uncovering how toxicants and stress stimuli impact the critical period of allocation during formative pluripotency, potentially influencing both the quantity and quality of PGCs. Furthermore, the comprehensive comparison of epigenetic events between mice and humans breaks new ground, empowering researchers to make informed decisions regarding the suitability of mouse models for their experiments.
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Affiliation(s)
- Aditi Singh
- CS Mott Center, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (A.S.); (D.A.R.)
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48202, USA
| | - Daniel A. Rappolee
- CS Mott Center, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (A.S.); (D.A.R.)
- Reproductive Stress Measurement, Mechanisms and Management, Corp., 135 Lake Shore Rd., Grosse Pointe Farms, MI 48236, USA
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA
- Department of Physiology, Wayne State University, Detroit, MI 48202, USA
| | - Douglas M. Ruden
- CS Mott Center, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; (A.S.); (D.A.R.)
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48202, USA
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USA
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6
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Krueger K, Lamenza F, Gu H, El-Hodiri H, Wester J, Oberdick J, Fischer AJ, Oghumu S. Sex differences in susceptibility to substance use disorder: Role for X chromosome inactivation and escape? Mol Cell Neurosci 2023; 125:103859. [PMID: 37207894 PMCID: PMC10286730 DOI: 10.1016/j.mcn.2023.103859] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 05/01/2023] [Accepted: 05/08/2023] [Indexed: 05/21/2023] Open
Abstract
There is a sex-based disparity associated with substance use disorders (SUDs) as demonstrated by clinical and preclinical studies. Females are known to escalate from initial drug use to compulsive drug-taking behavior (telescoping) more rapidly, and experience greater negative withdrawal effects than males. Although these biological differences have largely been attributed to sex hormones, there is evidence for non-hormonal factors, such as the influence of the sex chromosome, which underlie sex disparities in addiction behavior. However, genetic and epigenetic mechanisms underlying sex chromosome influences on substance abuse behavior are not completely understood. In this review, we discuss the role that escape from X-chromosome inactivation (XCI) in females plays in sex-associated differences in addiction behavior. Females have two X chromosomes (XX), and during XCI, one X chromosome is randomly chosen to be transcriptionally silenced. However, some X-linked genes escape XCI and display biallelic gene expression. We generated a mouse model using an X-linked gene specific bicistronic dual reporter mouse as a tool to visualize allelic usage and measure XCI escape in a cell specific manner. Our results revealed a previously undiscovered X-linked gene XCI escaper (CXCR3), which is variable and cell type dependent. This illustrates the highly complex and context dependent nature of XCI escape which is largely understudied in the context of SUD. Novel approaches such as single cell RNA sequencing will provide a global molecular landscape and impact of XCI escape in addiction and facilitate our understanding of the contribution of XCI escape to sex disparities in SUD.
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Affiliation(s)
- Kate Krueger
- Department of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Felipe Lamenza
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA
| | - Howard Gu
- Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA
| | - Heithem El-Hodiri
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| | - Jason Wester
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| | - John Oberdick
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| | - Andy J Fischer
- Department of Neuroscience, The Ohio State University, Columbus, OH, USA
| | - Steve Oghumu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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7
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Rosspopoff O, Cazottes E, Huret C, Loda A, Collier A, Casanova M, Rugg-Gunn P, Heard E, Ouimette JF, Rougeulle C. Species-specific regulation of XIST by the JPX/FTX orthologs. Nucleic Acids Res 2023; 51:2177-2194. [PMID: 36727460 PMCID: PMC10018341 DOI: 10.1093/nar/gkad029] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 12/08/2022] [Accepted: 01/11/2023] [Indexed: 02/03/2023] Open
Abstract
X chromosome inactivation (XCI) is an essential process, yet it initiates with remarkable diversity in various mammalian species. XIST, the main trigger of XCI, is controlled in the mouse by an interplay of lncRNA genes (LRGs), some of which evolved concomitantly to XIST and have orthologues across all placental mammals. Here, we addressed the functional conservation of human orthologues of two such LRGs, FTX and JPX. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in matched human and mouse pluripotent stem- or differentiated post-XCI cells, we demonstrate major functional differences for these orthologues between species, independently of primary sequence conservation. While the function of FTX is not conserved in humans, JPX stands as a major regulator of XIST expression in both species. However, we show that different entities of JPX control the production of XIST at various steps depending on the species. Altogether, our study highlights the functional versatility of LRGs across evolution, and reveals that functional conservation of orthologous LRGs may involve diversified mechanisms of action. These findings represent a striking example of how the evolvability of LRGs can provide adaptative flexibility to constrained gene regulatory networks.
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Affiliation(s)
- Olga Rosspopoff
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France
| | - Emmanuel Cazottes
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France
| | - Christophe Huret
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France
| | - Agnese Loda
- Directors' research, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Amanda J Collier
- Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK
- Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK
| | - Miguel Casanova
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France
| | - Peter J Rugg-Gunn
- Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK
- Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK
| | - Edith Heard
- Directors' research, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
- Collège de France, Paris, France
| | | | - Claire Rougeulle
- Université Paris Cité, CNRS, Epigenetics and Cell Fate, F-75013 Paris, France
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8
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Vargas LN, Silveira MM, Franco MM. Epigenetic Reprogramming and Somatic Cell Nuclear Transfer. Methods Mol Biol 2023; 2647:37-58. [PMID: 37041328 DOI: 10.1007/978-1-0716-3064-8_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2023]
Abstract
Epigenetics is an area of genetics that studies the heritable modifications in gene expression and phenotype that are not controlled by the primary sequence of DNA. The main epigenetic mechanisms are DNA methylation, post-translational covalent modifications in histone tails, and non-coding RNAs. During mammalian development, there are two global waves of epigenetic reprogramming. The first one occurs during gametogenesis and the second one begins immediately after fertilization. Environmental factors such as exposure to pollutants, unbalanced nutrition, behavioral factors, stress, in vitro culture conditions can negatively affect epigenetic reprogramming events. In this review, we describe the main epigenetic mechanisms found during mammalian preimplantation development (e.g., genomic imprinting, X chromosome inactivation). Moreover, we discuss the detrimental effects of cloning by somatic cell nuclear transfer on the reprogramming of epigenetic patterns and some molecular alternatives to minimize these negative impacts.
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Affiliation(s)
- Luna N Vargas
- Laboratory of Animal Reproduction, Embrapa Genetic Resources and Biotechnology, Brasília, Distrito Federal, Brazil
- Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
| | - Márcia M Silveira
- Laboratory of Animal Reproduction, Embrapa Genetic Resources and Biotechnology, Brasília, Distrito Federal, Brazil
- Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil
| | - Maurício M Franco
- Laboratory of Animal Reproduction, Embrapa Genetic Resources and Biotechnology, Brasília, Distrito Federal, Brazil.
- Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.
- School of Veterinary Medicine, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil.
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9
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The lncRNAs at X Chromosome Inactivation Center: Not Just a Matter of Sex Dosage Compensation. Int J Mol Sci 2022; 23:ijms23020611. [PMID: 35054794 PMCID: PMC8775829 DOI: 10.3390/ijms23020611] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/30/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
Non-coding RNAs (ncRNAs) constitute the majority of the transcriptome, as the result of pervasive transcription of the mammalian genome. Different RNA species, such as lncRNAs, miRNAs, circRNA, mRNAs, engage in regulatory networks based on their reciprocal interactions, often in a competitive manner, in a way denominated “competing endogenous RNA (ceRNA) networks” (“ceRNET”): miRNAs and other ncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs, titrating their availability and thus competing with the binding to other RNA targets. The unbalancing of any network component can derail the entire regulatory circuit acting as a driving force for human diseases, thus assigning “new” functions to “old” molecules. This is the case of XIST, the lncRNA characterized in the early 1990s and well known as the essential molecule for X chromosome inactivation in mammalian females, thus preventing an imbalance of X-linked gene expression between females and males. Currently, literature concerning XIST biology is becoming dominated by miRNA associations and they are also gaining prominence for other lncRNAs produced by the X-inactivation center. This review discusses the available literature to explore possible novel functions related to ceRNA activity of lncRNAs produced by the X-inactivation center, beyond their role in dosage compensation, with prospective implications for emerging gender-biased functions and pathological mechanisms.
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10
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Salama SR. The Complexity of the Mammalian Transcriptome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1363:11-22. [PMID: 35220563 DOI: 10.1007/978-3-030-92034-0_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Draft genome assemblies for multiple mammalian species combined with new technologies to map transcripts from diverse RNA samples to these genomes developed in the early 2000s revealed that the mammalian transcriptome was vastly larger and more complex than previously anticipated. Efforts to comprehensively catalog the identity and features of transcripts present in a variety of species, tissues and cell lines revealed that a large fraction of the mammalian genome is transcribed in at least some settings. A large number of these transcripts encode long non-coding RNAs (lncRNAs). Many lncRNAs overlap or are anti-sense to protein coding genes and others overlap small RNAs. However, a large number are independent of any previously known mRNA or small RNA. While the functions of a majority of these lncRNAs are unknown, many appear to play roles in gene regulation. Many lncRNAs have species-specific and cell type specific expression patterns and their evolutionary origins are varied. While technological challenges have hindered getting a full picture of the diversity and transcript structure of all of the transcripts arising from lncRNA loci, new technologies including single molecule nanopore sequencing and single cell RNA sequencing promise to generate a comprehensive picture of the mammalian transcriptome.
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Affiliation(s)
- Sofie R Salama
- UC Santa Cruz Genomics Institute, Department of Biomolecular Engineering and Howard Hughes Medical Institute, University of California, Santa Cruz, Santa Cruz, CA, USA.
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11
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Mofed D, Omran JI, Sabet S, Baiomy AA, Emara M, Salem TZ. The regulatory role of long non- coding RNAs as a novel controller of immune response against cancer cells. Mol Biol Rep 2022; 49:11775-11793. [PMID: 36207500 PMCID: PMC9712323 DOI: 10.1007/s11033-022-07947-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 09/14/2022] [Indexed: 02/01/2023]
Abstract
Immunotherapy has been established as a promising therapy for different cancer types. However, many patients experience primary or secondary resistance to treatment. Immune cells and anti-inflammatory factors are regulated by long noncoding RNAs (lncRNAs). In addition, lncRNAs have a role in immune resistance through antigen presentation loss or attenuation, PD-L1 upregulation, loss of T-cell activities, and activation of G-MDSCs and Tregs in the tumor environment. LncRNAs can also influence the interaction between cancer stem cells and immune cells in the tumor microenvironment, potentially resulting in cancer stem cell resistance to immunotherapy. Immunological-related lncRNAs can influence immune responses either directly by affecting neighboring protein-coding genes or indirectly by sponging miRNAs through various mechanisms. We have emphasized the role and levels of expression of lncRNAs that have been linked to immune cell formation, differentiation, and activation, which may have an influence on immunotherapy efficacy.
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Affiliation(s)
- Dina Mofed
- Molecular Biology and Virology lab, Biomedical Sciences Program, UST, Zewail City of Science and Technology, October Gardens, 6th of October City, 12578 Giza, Egypt
| | - Jihad I Omran
- Molecular Biology and Virology lab, Biomedical Sciences Program, UST, Zewail City of Science and Technology, October Gardens, 6th of October City, 12578 Giza, Egypt
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Ahmed A Baiomy
- Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt
| | - Marwan Emara
- Center for Aging and Associated Diseases, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, 12578 Giza, Egypt
| | - Tamer Z. Salem
- Molecular Biology and Virology lab, Biomedical Sciences Program, UST, Zewail City of Science and Technology, October Gardens, 6th of October City, 12578 Giza, Egypt
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12
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Blasiak J, Hyttinen JMT, Szczepanska J, Pawlowska E, Kaarniranta K. Potential of Long Non-Coding RNAs in Age-Related Macular Degeneration. Int J Mol Sci 2021; 22:9178. [PMID: 34502084 PMCID: PMC8431062 DOI: 10.3390/ijms22179178] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/16/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with poorly known pathogenesis and lack of effective treatment. Age and family history are the strongest AMD risk factors, and several loci were identified to contribute to AMD. Recently, also the epigenetic profile was associated with AMD, and some long non-coding RNAs (lncRNAs) were shown to involve in AMD pathogenesis. The Vax2os1/2 (ventral anterior homeobox 2 opposite strand isoform 1) lncRNAs may modulate the balance between pro- and anti-angiogenic factors in the eye contributing to wet AMD. The stress-induced dedifferentiation of retinal pigment epithelium cells can be inhibited by the ZNF503-AS1 (zinc finger protein 503 antisense RNA 2) and LINC00167 lncRNAs. Overexpression of the PWRN2 (Prader-Willi region non-protein-coding RNA 2) lncRNA aggravated RPE cells apoptosis and mitochondrial impairment induced by oxidative stress. Several other lncRNAs were reported to exert protective or detrimental effects in AMD. However, many studies are limited to an association between lncRNA and AMD in patients or model systems with bioinformatics. Therefore, further works on lncRNAs in AMD are rational, and they should be enriched with mechanistic and clinical studies to validate conclusions obtained in high-throughput in vitro research.
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Affiliation(s)
- Janusz Blasiak
- Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland
| | - Juha M. T. Hyttinen
- Department of Ophthalmology, University of Eastern Finland, 70210 Kuopio, Finland;
| | - Joanna Szczepanska
- Department of Pediatric Dentistry, Medical University of Lodz, 92-216 Lodz, Poland;
| | - Elzbieta Pawlowska
- Department of Orthodontics, Medical University of Lodz, 92-217 Lodz, Poland;
| | - Kai Kaarniranta
- Department of Ophthalmology, University of Eastern Finland, 70210 Kuopio, Finland;
- Department of Ophthalmology, Kuopio University Hospital, 70210 Kuopio, Finland
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13
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Wang W, Min L, Qiu X, Wu X, Liu C, Ma J, Zhang D, Zhu L. Biological Function of Long Non-coding RNA (LncRNA) Xist. Front Cell Dev Biol 2021; 9:645647. [PMID: 34178980 PMCID: PMC8222981 DOI: 10.3389/fcell.2021.645647] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) regulate gene expression in a variety of ways at epigenetic, chromatin remodeling, transcriptional, and translational levels. Accumulating evidence suggests that lncRNA X-inactive specific transcript (lncRNA Xist) serves as an important regulator of cell growth and development. Despites its original roles in X-chromosome dosage compensation, lncRNA Xist also participates in the development of tumor and other human diseases by functioning as a competing endogenous RNA (ceRNA). In this review, we comprehensively summarized recent progress in understanding the cellular functions of lncRNA Xist in mammalian cells and discussed current knowledge regarding the ceRNA network of lncRNA Xist in various diseases. Long non-coding RNAs (lncRNAs) are transcripts that are more than 200 nt in length and without an apparent protein-coding capacity (Furlan and Rougeulle, 2016; Maduro et al., 2016). These RNAs are believed to be transcribed by the approximately 98-99% non-coding regions of the human genome (Derrien et al., 2012; Fu, 2014; Montalbano et al., 2017; Slack and Chinnaiyan, 2019), as well as a large variety of genomic regions, such as exonic, tronic, and intergenic regions. Hence, lncRNAs are also divided into eight categories: Intergenic lncRNAs, Intronic lncRNAs, Enhancer lncRNAs, Promoter lncRNAs, Natural antisense/sense lncRNAs, Small nucleolar RNA-ended lncRNAs (sno-lncRNAs), Bidirectional lncRNAs, and non-poly(A) lncRNAs (Ma et al., 2013; Devaux et al., 2015; St Laurent et al., 2015; Chen, 2016; Quinn and Chang, 2016; Richard and Eichhorn, 2018; Connerty et al., 2020). A range of evidence has suggested that lncRNAs function as key regulators in crucial cellular functions, including proliferation, differentiation, apoptosis, migration, and invasion, by regulating the expression level of target genes via epigenomic, transcriptional, or post-transcriptional approaches (Cao et al., 2018). Moreover, lncRNAs detected in body fluids were also believed to serve as potential biomarkers for the diagnosis, prognosis, and monitoring of disease progression, and act as novel and potential drug targets for therapeutic exploitation in human disease (Jiang W. et al., 2018; Zhou et al., 2019a). Long non-coding RNA X-inactive specific transcript (lncRNA Xist) are a set of 15,000-20,000 nt sequences localized in the X chromosome inactivation center (XIC) of chromosome Xq13.2 (Brown et al., 1992; Debrand et al., 1998; Kay, 1998; Lee et al., 2013; da Rocha and Heard, 2017; Yang Z. et al., 2018; Brockdorff, 2019). Previous studies have indicated that lncRNA Xist regulate X chromosome inactivation (XCI), resulting in the inheritable silencing of one of the X-chromosomes during female cell development. Also, it serves a vital regulatory function in the whole spectrum of human disease (notably cancer) and can be used as a novel diagnostic and prognostic biomarker and as a potential therapeutic target for human disease in the clinic (Liu et al., 2018b; Deng et al., 2019; Dinescu et al., 2019; Mutzel and Schulz, 2020; Patrat et al., 2020; Wang et al., 2020a). In particular, lncRNA Xist have been demonstrated to be involved in the development of multiple types of tumors including brain tumor, Leukemia, lung cancer, breast cancer, and liver cancer, with the prominent examples outlined in Table 1. It was also believed that lncRNA Xist (Chaligne and Heard, 2014; Yang Z. et al., 2018) contributed to other diseases, such as pulmonary fibrosis, inflammation, neuropathic pain, cardiomyocyte hypertrophy, and osteoarthritis chondrocytes, and more specific details can be found in Table 2. This review summarizes the current knowledge on the regulatory mechanisms of lncRNA Xist on both chromosome dosage compensation and pathogenesis (especially cancer) processes, with a focus on the regulatory network of lncRNA Xist in human disease.
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Affiliation(s)
| | | | | | | | | | | | - Dongyi Zhang
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, China
| | - Lingyun Zhu
- Department of Biology and Chemistry, College of Liberal Arts and Sciences, National University of Defense Technology, Changsha, China
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14
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Bansal P, Ahern DT, Kondaveeti Y, Qiu CW, Pinter SF. Contiguous erosion of the inactive X in human pluripotency concludes with global DNA hypomethylation. Cell Rep 2021; 35:109215. [PMID: 34107261 PMCID: PMC8267460 DOI: 10.1016/j.celrep.2021.109215] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 08/18/2020] [Accepted: 05/13/2021] [Indexed: 01/21/2023] Open
Abstract
Female human pluripotent stem cells (hPSCs) routinely undergo inactive X (Xi) erosion. This progressive loss of key repressive features follows the loss of XIST expression, the long non-coding RNA driving X inactivation, and causes reactivation of silenced genes across the eroding X (Xe). To date, the sporadic and progressive nature of erosion has obscured its scale, dynamics, and key transition events. To address this problem, we perform an integrated analysis of DNA methylation (DNAme), chromatin accessibility, and gene expression across hundreds of hPSC samples. Differential DNAme orders female hPSCs across a trajectory from initiation to terminal Xi erosion. Our results identify a cis-regulatory element crucial for XIST expression, trace contiguously growing reactivated domains to a few euchromatic origins, and indicate that the late-stage Xe impairs DNAme genome-wide. Surprisingly, from this altered regulatory landscape emerge select features of naive pluripotency, suggesting that its link to X dosage may be partially conserved in human embryonic development. Reactivation of the silenced X in human female iPSC/ESCs compromises their utility. Bansal et al. perform an integrated genomics analysis to reveal a prevalent X erosion trajectory that they validate in long-term culture. Starting with XIST loss, this trajectory indicates that reactivation may spread contiguously from escapees to silenced genes.
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Affiliation(s)
- Prakhar Bansal
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Darcy T Ahern
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Yuvabharath Kondaveeti
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Catherine W Qiu
- Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA
| | - Stefan F Pinter
- Graduate Program in Genetics and Developmental Biology, UCONN Health, University of Connecticut, Farmington, CT, USA; Department of Genetics and Genome Sciences, UCONN Health, University of Connecticut, Farmington, CT, USA; Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA.
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15
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Abstract
We have known for decades that long noncoding RNAs (lncRNAs) can play essential functions across most forms of life. The maintenance of chromosome length requires an lncRNA (e.g., hTERC) and two lncRNAs in the ribosome that are required for protein synthesis. Thus, lncRNAs can represent powerful RNA machines. More recently, it has become clear that mammalian genomes encode thousands more lncRNAs. Thus, we raise the question: Which, if any, of these lncRNAs could also represent RNA-based machines? Here we synthesize studies that are beginning to address this question by investigating fundamental properties of lncRNA genes, revealing new insights into the RNA structure-function relationship, determining cis- and trans-acting lncRNAs in vivo, and generating new developments in high-throughput screening used to identify functional lncRNAs. Overall, these findings provide a context toward understanding the molecular grammar underlying lncRNA biology.
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Affiliation(s)
- John L Rinn
- BioFrontiers Institute, Department of Biochemistry, University of Colorado, Boulder, Colorado 80303, USA;
| | - Howard Y Chang
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, California 94305, USA.,Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA
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16
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Chaudhary R. Potential of long non-coding RNAs as a therapeutic target and molecular markers in glioblastoma pathogenesis. Heliyon 2021; 7:e06502. [PMID: 33786397 PMCID: PMC7988331 DOI: 10.1016/j.heliyon.2021.e06502] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/20/2020] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma (GB) is by far the most hostile type of malignant tumor that primarily affects the brain and spine, derived from star-shaped glial cells that are astrocytes and oligodendrocytes. Despite of significant efforts in recent years in glioblastoma research, the clinical efficacy of existing medical intervention is still limited and very few potential diagnostic markers are available. Long non-coding RNAs (lncRNAs) that lacks protein-coding capabilities were previously thought to be "junk sequences" in mammalian genomes are quite indispensible epigenetic regulators that can positively or negatively regulate gene expression and nuclear architecture, with significant roles in the initiation and development of tumors. Nevertheless, the precise mechanism of these distortedly expressed lncRNAs in glioblastoma pathogenesis is not yet fully understood. Since the advent of high-throughput sequencing technologies, more and more research have elucidated that lncRNAs are one of the most promising prognostic biomarkers and therapeutic targets for glioblastoma. In this paper, I briefly outlined the existing findings of lncRNAs. And also summarizes the profiles of different lncRNAs that have been broadly classified in glioblastoma research, with emphasis on both their prognostic and therapeutic values.
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Affiliation(s)
- Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow 226025, U.P., India
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17
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Chen J, Li X, Yang L, Zhang J. Long Non-coding RNA LINC01969 Promotes Ovarian Cancer by Regulating the miR-144-5p/LARP1 Axis as a Competing Endogenous RNA. Front Cell Dev Biol 2021; 8:625730. [PMID: 33614632 PMCID: PMC7889973 DOI: 10.3389/fcell.2020.625730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 12/28/2020] [Indexed: 12/19/2022] Open
Abstract
Accumulating evidence has shown that long non-coding RNAs (lncRNAs) can be used as biological markers and treatment targets in cancer and play various roles in cancer-related biological processes. However, the lncRNA expression profiles and their roles and action mechanisms in ovarian cancer (OC) are largely unknown. Here, we assessed the lncRNA expression profiles in OC tissues from The Cancer Genome Atlas (TCGA) database, and one upregulated lncRNA, LINC01969, was selected for further study. LINC01969 expression levels in 41 patients were verified using quantitative real-time polymerase chain reaction (qRT-PCR). The in vitro effects of LINC01969 on OC cell migration, invasion, and proliferation were determined by the CCK-8, ethynyl-2-deoxyuridine (EdU), wound healing, and Transwell assays. Epithelial–mesenchymal transition (EMT) was evaluated using qRT-PCR and Western blotting. The molecular mechanisms of LINC01969 in OC were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation (RIP), dual luciferase reporter gene assays, and a rescue experiment. Finally, in vivo experiments were conducted to evaluate the functions of LINC01969. The results of the current study showed that LINC01969 was dramatically upregulated in OC, and patients with lower LINC01969 expression levels tended to have better overall survival. Further experiments demonstrated that LINC01969 promoted the migration, invasion, and proliferation of OC cells in vitro and sped up tumor growth in vivo. Additionally, LINC01969, which primarily exists in the cytoplasm, boosted LARP1 expression by sponging miR-144-5p and promoted the malignant phenotypes of OC cells. In conclusion, the LINC01969/miR-144-5p/LARP1 axis is a newly identified regulatory signaling pathway involved in OC progression.
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Affiliation(s)
- Jinxin Chen
- Department of Gynecology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Xiaocen Li
- Department of Graduate School, Dalian Medical University, Dalian, China
| | - Lu Yang
- Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
| | - Jingru Zhang
- Department of Gynecology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, China
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18
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Patrat C, Ouimette JF, Rougeulle C. X chromosome inactivation in human development. Development 2020; 147:147/1/dev183095. [PMID: 31900287 DOI: 10.1242/dev.183095] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
X chromosome inactivation (XCI) is a key developmental process taking place in female mammals to compensate for the imbalance in the dosage of X-chromosomal genes between sexes. It is a formidable example of concerted gene regulation and a paradigm for epigenetic processes. Although XCI has been substantially deciphered in the mouse model, how this process is initiated in humans has long remained unexplored. However, recent advances in the experimental capacity to access human embryonic-derived material and in the laws governing ethical considerations of human embryonic research have allowed us to enlighten this black box. Here, we will summarize the current knowledge of human XCI, mainly based on the analyses of embryos derived from in vitro fertilization and of pluripotent stem cells, and highlight any unanswered questions.
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Affiliation(s)
- Catherine Patrat
- Université de Paris, UMR 1016, Institut Cochin, 75014 Paris, France .,Service de Biologie de la Reproduction - CECOS, Paris Centre Hospital, APHP.centre, 75014 Paris, France
| | | | - Claire Rougeulle
- Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013 Paris, France
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19
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Casanova M, Moscatelli M, Chauvière LÉ, Huret C, Samson J, Liyakat Ali TM, Rosspopoff O, Rougeulle C. A primate-specific retroviral enhancer wires the XACT lncRNA into the core pluripotency network in humans. Nat Commun 2019; 10:5652. [PMID: 31827084 PMCID: PMC6906429 DOI: 10.1038/s41467-019-13551-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 11/05/2019] [Indexed: 12/22/2022] Open
Abstract
Transposable elements (TEs) have been proposed to play an important role in driving the expansion of gene regulatory networks during mammalian evolution, notably by contributing to the evolution and function of long non-coding RNAs (lncRNAs). XACT is a primate-specific TE-derived lncRNA that coats active X chromosomes in pluripotent cells and may contribute to species-specific regulation of X-chromosome inactivation. Here we explore how different families of TEs have contributed to shaping the XACT locus and coupling its expression to pluripotency. Through a combination of sequence analysis across primates, transcriptional interference, and genome editing, we identify a critical enhancer for the regulation of the XACT locus that evolved from an ancestral group of mammalian endogenous retroviruses (ERVs), prior to the emergence of XACT. This ERV was hijacked by younger hominoid-specific ERVs that gave rise to the promoter of XACT, thus wiring its expression to the pluripotency network. This work illustrates how retroviral-derived sequences may intervene in species-specific regulatory pathways.
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Affiliation(s)
- Miguel Casanova
- Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013, Paris, France.
| | | | | | - Christophe Huret
- Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013, Paris, France
| | - Julia Samson
- Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013, Paris, France
| | | | - Olga Rosspopoff
- Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013, Paris, France
| | - Claire Rougeulle
- Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013, Paris, France.
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20
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Shi FT, Chen LD, Zhang LF. Long Noncoding RNA UCA1 Overexpression Is Associated with Poor Prognosis in Digestive System Malignancies: A Meta-analysis. Curr Med Sci 2019; 39:694-701. [PMID: 31612385 DOI: 10.1007/s11596-019-2094-3] [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: 05/09/2019] [Revised: 09/03/2019] [Indexed: 10/25/2022]
Abstract
Long noncoding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) has been reported to be highly expressed in many kinds of cancers. This meta-analysis summarized its potential prognostic value in digestive system malignancies. A meta-analysis was performed through a comprehensive search in PubMed, EMBASE, the Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI) for suitable articles on the prognostic impact of UCA1 in digestive system malignancies from inception to June 27, 2019. Pooled hazard ratios (HRs) with 95% confidence interval (95%CI) were calculated to summarize the effect. Sixteen studies were included in the study, with a total of 1504 patients. A significant association was observed between UCA1 abundance and poor overall survival (OS), and shorter disease-free survival (DFS) for patients with digestive system malignancies, with pooled HR of 2.07 (95%CI: 1.74-2.47), and of 2.50 (95%CI: 1.62-3.86). Subgroup analysis and sensitivity analysis suggested the reliability of our findings. It is suggested that UCA1 abundance may serve as a reliable predictive factor for poor prognosis in patients with digestive system malignancies.
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Affiliation(s)
- Fei-Tao Shi
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Li-Dong Chen
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Lian-Feng Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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21
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Abstract
In mammals, dosage compensation of sex chromosomal genes between females (XX) and males (XY) is achieved through X-chromosome inactivation (XCI). The X-linked X-inactive-specific transcript (Xist) long noncoding RNA is indispensable for XCI and initiates the process early during development by spreading in cis across the X chromosome from which it is transcribed. During XCI, Xist RNA triggers gene silencing, recruits a plethora of chromatin modifying factors, and drives a major structural reorganization of the X chromosome. Here, we review our knowledge of the multitude of epigenetic events orchestrated by Xist RNA to allow female mammals to survive through embryonic development by establishing and maintaining proper dosage compensation. In particular, we focus on recent studies characterizing the interaction partners of Xist RNA, and we discuss how they have affected the field by addressing long-standing controversies or by giving rise to new research perspectives that are currently being explored. This review is dedicated to the memory of Denise Barlow, pioneer of genomic imprinting and functional long noncoding RNAs (lncRNAs), whose work has revolutionized the epigenetics field and continues to inspire generations of scientists.
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22
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Mendonça ADS, Silveira MM, Rios ÁFL, Mangiavacchi PM, Caetano AR, Dode MAN, Franco MM. DNA methylation and functional characterization of the XIST gene during in vitro early embryo development in cattle. Epigenetics 2019; 14:568-588. [PMID: 30925851 DOI: 10.1080/15592294.2019.1600828] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
XIST, in association with the shorter ncRNA RepA, are essential for the initiation of X chromosome inactivation (XCI) in mice. The molecular mechanisms controlling XIST and RepA expression are well characterized in that specie. However, little is known in livestock. We aimed to characterize the DNA methylation status along the 5' portion of XIST and to characterize its transcriptional profile during early development in cattle. Three genomic regions of XIST named here as promoter, RepA and DMR1 had their DNA methylation status characterized in gametes and embryos. Expression profile of XIST was evaluated, including sense and antisense transcription. Oocytes showed higher levels of methylation than spermatozoa that was demethylated. DMR1 was hypermethylated throughout oogenesis. At the 8-16-cell embryo stage DMR1 was completed demethylated. Interestingly, RepA gain methylation during oocyte maturation and was demethylated at the blastocyst stage, later than DMR1. These results suggest that DMR1 and RepA are transient differentially methylated regions in cattle. XIST RNA was detected in matured oocytes and in single cells from the 2-cell to the morula stage, confirming the presence of maternal and embryonic transcripts. Sense and antisense transcripts were detected along the XIST in blastocyst. In silico analysis identified 63 novel transcript candidates at bovine XIST locus from both the plus and minus strands. Taking together these results improve our understanding of the molecular mechanisms involved in XCI initiation in cattle. This information may be useful for the improvement of assisted reproductive technologies in livestock considering that in vitro conditions may impair epigenetic reprogramming.
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Affiliation(s)
- Anelise Dos Santos Mendonça
- a Laboratory of Animal Reproduction, Embrapa Genetic Resources and Biotechnology , Parque Estação Biológica , Brasília , Brazil.,b Institute of Genetics and Biochemistry , Federal University of Uberlândia , Umuarama , Brazil.,c Federal Institute of Education, Science and Technology of Piauí , Uruçuí Campus , Portal dos Cerrados , Brazil
| | - Márcia Marques Silveira
- a Laboratory of Animal Reproduction, Embrapa Genetic Resources and Biotechnology , Parque Estação Biológica , Brasília , Brazil.,b Institute of Genetics and Biochemistry , Federal University of Uberlândia , Umuarama , Brazil
| | - Álvaro Fabrício Lopes Rios
- d Biotechnology Laboratory, Center of Biosciences and Biotechnology , North Fluminense State University , Campos dos Goytacazes , Brazil
| | - Paula Magnelli Mangiavacchi
- e Laboratory of Reproduction and Animal Genetic Improvement, Center for Agricultural Sciences and Technologies , North Fluminense State University , Campos dos Goytacazes , Brazil
| | - Alexandre Rodrigues Caetano
- f Embrapa Genetic Resources and Biotechnology , Parque Estação Biológica , Brasília , Brazil.,g School of Agriculture and Veterinary Medicine , University of Brasília, Darcy Ribeiro Campus , Brasília , Brazil
| | - Margot Alves Nunes Dode
- a Laboratory of Animal Reproduction, Embrapa Genetic Resources and Biotechnology , Parque Estação Biológica , Brasília , Brazil.,g School of Agriculture and Veterinary Medicine , University of Brasília, Darcy Ribeiro Campus , Brasília , Brazil
| | - Maurício Machaim Franco
- a Laboratory of Animal Reproduction, Embrapa Genetic Resources and Biotechnology , Parque Estação Biológica , Brasília , Brazil.,b Institute of Genetics and Biochemistry , Federal University of Uberlândia , Umuarama , Brazil.,h Faculty of Veterinary Medicine , Federal University of Uberlândia , Umuarama , Brazil
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23
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Pyfrom SC, Luo H, Payton JE. PLAIDOH: a novel method for functional prediction of long non-coding RNAs identifies cancer-specific LncRNA activities. BMC Genomics 2019; 20:137. [PMID: 30767760 PMCID: PMC6377765 DOI: 10.1186/s12864-019-5497-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 01/29/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) exhibit remarkable cell-type specificity and disease association. LncRNA's functional versatility includes epigenetic modification, nuclear domain organization, transcriptional control, regulation of RNA splicing and translation, and modulation of protein activity. However, most lncRNAs remain uncharacterized due to a shortage of predictive tools available to guide functional experiments. RESULTS To address this gap for lymphoma-associated lncRNAs identified in our studies, we developed a new computational method, Predicting LncRNA Activity through Integrative Data-driven 'Omics and Heuristics (PLAIDOH), which has several unique features not found in other methods. PLAIDOH integrates transcriptome, subcellular localization, enhancer landscape, genome architecture, chromatin interaction, and RNA-binding (eCLIP) data and generates statistically defined output scores. PLAIDOH's approach identifies and ranks functional connections between individual lncRNA, coding gene, and protein pairs using enhancer, transcript cis-regulatory, and RNA-binding protein interactome scores that predict the relative likelihood of these different lncRNA functions. When applied to 'omics datasets that we collected from lymphoma patients, or to publicly available cancer (TCGA) or ENCODE datasets, PLAIDOH identified and prioritized well-known lncRNA-target gene regulatory pairs (e.g., HOTAIR and HOX genes, PVT1 and MYC), validated hits in multiple lncRNA-targeted CRISPR screens, and lncRNA-protein binding partners (e.g., NEAT1 and NONO). Importantly, PLAIDOH also identified novel putative functional interactions, including one lymphoma-associated lncRNA based on analysis of data from our human lymphoma study. We validated PLAIDOH's predictions for this lncRNA using knock-down and knock-out experiments in lymphoma cell models. CONCLUSIONS Our study demonstrates that we have developed a new method for the prediction and ranking of functional connections between individual lncRNA, coding gene, and protein pairs, which were validated by genetic experiments and comparison to published CRISPR screens. PLAIDOH expedites validation and follow-on mechanistic studies of lncRNAs in any biological system. It is available at https://github.com/sarahpyfrom/PLAIDOH .
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Affiliation(s)
- Sarah C. Pyfrom
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Hong Luo
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Jacqueline E. Payton
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 USA
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24
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Furlan G, Gutierrez Hernandez N, Huret C, Galupa R, van Bemmel JG, Romito A, Heard E, Morey C, Rougeulle C. The Ftx Noncoding Locus Controls X Chromosome Inactivation Independently of Its RNA Products. Mol Cell 2019; 70:462-472.e8. [PMID: 29706539 DOI: 10.1016/j.molcel.2018.03.024] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 02/21/2018] [Accepted: 03/22/2018] [Indexed: 01/26/2023]
Abstract
Accumulation of the Xist long noncoding RNA (lncRNA) on one X chromosome is the trigger for X chromosome inactivation (XCI) in female mammals. Xist expression, which needs to be tightly controlled, involves a cis-acting region, the X-inactivation center (Xic), containing many lncRNA genes that evolved concomitantly to Xist from protein-coding ancestors through pseudogeneization and loss of coding potential. Here, we uncover an essential role for the Xic-linked noncoding gene Ftx in the regulation of Xist expression. We show that Ftx is required in cis to promote Xist transcriptional activation and establishment of XCI. Importantly, we demonstrate that this function depends on Ftx transcription and not on the RNA products. Our findings illustrate the multiplicity of layers operating in the establishment of XCI and highlight the diversity in the modus operandi of the noncoding players.
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Affiliation(s)
- Giulia Furlan
- Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Université Paris Diderot, Paris, France
| | - Nancy Gutierrez Hernandez
- Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Université Paris Diderot, Paris, France
| | - Christophe Huret
- Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Université Paris Diderot, Paris, France
| | - Rafael Galupa
- Institut Curie, PSL Research University, CNRS, INSERM, UMR3215/U934 Genetics and Developmental Biology Unit, Mammalian Developmental Epigenetics Group, F-75005 Paris, France
| | - Joke Gerarda van Bemmel
- Institut Curie, PSL Research University, CNRS, INSERM, UMR3215/U934 Genetics and Developmental Biology Unit, Mammalian Developmental Epigenetics Group, F-75005 Paris, France; Department of Developmental Biology, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, the Netherlands
| | - Antonio Romito
- Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Université Paris Diderot, Paris, France
| | - Edith Heard
- Institut Curie, PSL Research University, CNRS, INSERM, UMR3215/U934 Genetics and Developmental Biology Unit, Mammalian Developmental Epigenetics Group, F-75005 Paris, France
| | - Céline Morey
- Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Université Paris Diderot, Paris, France.
| | - Claire Rougeulle
- Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, Université Paris Diderot, Paris, France.
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REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice. Nat Commun 2018; 9:4752. [PMID: 30420655 PMCID: PMC6232137 DOI: 10.1038/s41467-018-07060-w] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 10/05/2018] [Indexed: 01/15/2023] Open
Abstract
In mice, imprinted X chromosome inactivation (iXCI) of the paternal X in the pre-implantation embryo and extraembryonic tissues is followed by X reactivation in the inner cell mass (ICM) of the blastocyst to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic lethality due to iXCI failure. Here, we show that loss of Rex1 rescues the rXCI phenotype observed in Rnf12−/− ESCs, and that REX1 is the prime target of RNF12 in ESCs. Genetic ablation of Rex1 in Rnf12−/− mice rescues the Rnf12−/− iXCI phenotype, and results in viable and fertile Rnf12−/−:Rex1−/− female mice displaying normal iXCI and rXCI. Our results show that REX1 is the critical target of RNF12 in XCI. REX1 has been shown to regulate pluripotency of ESCs, genomic imprinting and preimplantation development in mice. Here the authors provide evidence that REX1 is the prime target of RNF12 E3 ubiquitin ligase and that Rex1 removal rescues the Rnf12 knockout phenotype in imprinted X chromosome inactivation in mice.
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26
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Female mice lacking Ftx lncRNA exhibit impaired X-chromosome inactivation and a microphthalmia-like phenotype. Nat Commun 2018; 9:3829. [PMID: 30237402 PMCID: PMC6148026 DOI: 10.1038/s41467-018-06327-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 08/24/2018] [Indexed: 01/08/2023] Open
Abstract
X-chromosome inactivation (XCI) is an essential epigenetic process in female mammalian development. Although cell-based studies suggest the potential importance of the Ftx long non-protein-coding RNA (lncRNA) in XCI, its physiological roles in vivo remain unclear. Here we show that targeted deletion of X-linked mouse Ftx lncRNA causes eye abnormalities resembling human microphthalmia in a subset of females but rarely in males. This inheritance pattern cannot be explained by X-linked dominant or recessive inheritance, where males typically show a more severe phenotype than females. In Ftx-deficient mice, some X-linked genes remain active on the inactive X, suggesting that defects in random XCI in somatic cells cause a substantially female-specific phenotype. The expression level of Xist, a master regulator of XCI, is diminished in females homozygous or heterozygous for Ftx deficiency. We propose that loss-of-Ftx lncRNA abolishes gene silencing on the inactive X chromosome, leading to a female microphthalmia-like phenotype. Although Ftx lncRNA has been linked to X-chromosome inactivation, its physiological roles in vivo remain unclear. Here the authors show that deletion of mouse Ftx causes eye abnormalities similar to human microphthalmia in a subset of female mice but rarely in males and provide evidence that Ftx plays a role in gene silencing on the inactive X chromosome.
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27
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Hanna CW, Demond H, Kelsey G. Epigenetic regulation in development: is the mouse a good model for the human? Hum Reprod Update 2018; 24:556-576. [PMID: 29992283 PMCID: PMC6093373 DOI: 10.1093/humupd/dmy021] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/20/2018] [Accepted: 06/05/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Over the past few years, advances in molecular technologies have allowed unprecedented mapping of epigenetic modifications in gametes and during early embryonic development. This work is allowing a detailed genomic analysis, which for the first time can answer long-standing questions about epigenetic regulation and reprogramming, and highlights differences between mouse and human, the implications of which are only beginning to be explored. OBJECTIVE AND RATIONALE In this review, we summarise new low-cell molecular methods enabling the interrogation of epigenetic information in gametes and early embryos, the mechanistic insights these have provided, and contrast the findings in mouse and human. SEARCH METHODS Relevant studies were identified by PubMed search. OUTCOMES We discuss the levels of epigenetic regulation, from DNA modifications to chromatin organisation, during mouse gametogenesis, fertilisation and pre- and post-implantation development. The recently characterised features of the oocyte epigenome highlight its exceptionally unique regulatory landscape. The chromatin organisation and epigenetic landscape of both gametic genomes are rapidly reprogrammed after fertilisation. This extensive epigenetic remodelling is necessary for zygotic genome activation, but the mechanistic link remains unclear. While the vast majority of epigenetic information from the gametes is erased in pre-implantation development, new insights suggest that repressive histone modifications from the oocyte may mediate a novel mechanism of imprinting. To date, the characterisation of epigenetics in human development has been almost exclusively limited to DNA methylation profiling; these data reinforce that the global dynamics are conserved between mouse and human. However, as we look closer, it is becoming apparent that the mechanisms regulating these dynamics are distinct. These early findings emphasise the importance of investigations of fundamental epigenetic mechanisms in both mouse and humans. WIDER IMPLICATIONS Failures in epigenetic regulation have been implicated in human disease and infertility. With increasing maternal age and use of reproductive technologies in countries all over the world, it is becoming ever more important to understand the necessary processes required to establish a developmentally competent embryo. Furthermore, it is essential to evaluate the extent to which these epigenetic patterns are sensitive to such technologies and other adverse environmental exposures.
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Affiliation(s)
- Courtney W Hanna
- Epigenetics programme, Babraham Institute, Cambridge, UK
- Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
| | - Hannah Demond
- Epigenetics programme, Babraham Institute, Cambridge, UK
| | - Gavin Kelsey
- Epigenetics programme, Babraham Institute, Cambridge, UK
- Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
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Yan F, Wang X, Zeng Y. 3D genomic regulation of lncRNA and Xist in X chromosome. Semin Cell Dev Biol 2018; 90:174-180. [PMID: 30017906 DOI: 10.1016/j.semcdb.2018.07.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 01/19/2023]
Abstract
Long noncoding RNAs (lncRNAs) act as important regulators in cardiovascular diseases, neural degenerative disease, or cancers, by localizing and spreading across chromatins. lncRNA can regulate the 3D architecture of the enhancer cluster at the target gene locus, relevant to analogous lncRNA-protein coding gene pairs. X inactive specific transcript (Xist) plays a critical role in the process and biological function of lncRNAs. The lncRNA Jpx, Xist activator, is a nonprotein-coding RNA transcribed from a gene within the X-inactivation center and acts as a numerator element to control X-chromosome number and activate Xist transcription by interacting with CCCTC-binding factor. Up-regulated lncRNA Xist initiates X chromosome inactivation process and attracts specific chromatin modifiers. A number of chromatin-modified factors interact with lncRNAs modify 3D genome architecture and mediate Xist function in embryo development. Thus, the regulation of lncRNAs in 3D genome progresses is the key mechanism of Xist, as a therapeutic potential for Xist associated diseases.
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Affiliation(s)
- Furong Yan
- Center for Molecular Diagnosis and Therapy, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Xiangdong Wang
- Center for Molecular Diagnosis and Therapy, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China.
| | - Yiming Zeng
- Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital of Fujian Medical University, Respiratory Medicine Center of Fujian Province, Quanzhou, Fujian Province, China.
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29
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Targeting the IGF1R Pathway in Breast Cancer Using Antisense lncRNA-Mediated Promoter cis Competition. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 12:105-117. [PMID: 30195750 PMCID: PMC6023958 DOI: 10.1016/j.omtn.2018.04.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 04/26/2018] [Accepted: 04/27/2018] [Indexed: 02/06/2023]
Abstract
Aberrant insulin-like growth factor I receptor (IGF1R) signaling pathway serves as a well-established target for cancer drug therapy. The intragenic antisense long noncoding RNA (lncRNA) IRAIN, a putative tumor suppressor, is downregulated in breast cancer cells, while IGF1R is overexpressed, leading to an abnormal IGF1R/IRAIN ratio that promotes tumor growth. To precisely target this pathway, we developed an “antisense lncRNA-mediated intragenic cis competition” (ALIC) approach to therapeutically correct the elevated IGF1R/IRAIN bias in breast cancer cells. We used CRISPR-Cas9 gene editing to target the weak promoter of IRAIN antisense lncRNA and showed that in targeted clones, intragenic activation of the antisense lncRNA potently competed in cis with the promoter of the IGF1R sense mRNA. Notably, the normalization of IGF1R/IRAIN transcription inhibited the IGF1R signaling pathway in breast cancer cells, decreasing cell proliferation, tumor sphere formation, migration, and invasion. Using “nuclear RNA reverse transcription-associated trap” sequencing, we uncovered an IRAIN lncRNA-specific interactome containing gene targets involved in cell metastasis, signaling pathways, and cell immortalization. These data suggest that aberrantly upregulated IGF1R in breast cancer cells can be precisely targeted by cis transcription competition, thus providing a useful strategy to target disease genes in the development of novel precision medicine therapies.
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30
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Li M, Wang Y, Cheng L, Niu W, Zhao G, Raju JK, Huo J, Wu B, Yin B, Song Y, Bu R. Long non-coding RNAs in renal cell carcinoma: A systematic review and clinical implications. Oncotarget 2018; 8:48424-48435. [PMID: 28467794 PMCID: PMC5564659 DOI: 10.18632/oncotarget.17053] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 03/20/2017] [Indexed: 12/27/2022] Open
Abstract
Renal cell carcinoma is one of the most common malignancy in adults, its prognosis is poor in an advanced stage and early detection is difficult due to the lack of molecular biomarkers. The identification of novel biomarkers for RCC is an urgent and meaningful project. Long non-coding RNA (lncRNA) is transcribed from genomic regions with a minimum length of 200 bases and limited protein-coding potential. Recently, lncRNAs have been greatly studied in a variety of cancer types. They participate in a wide variety of biological processes including cancer biology. In this review, we provide a new insight of the profiling of lncRNAs in RCC and their roles in renal carcinogenesis, with an emphasize on their potential in diagnosis, prognosis and potential roles in RCC therapy.
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Affiliation(s)
- Ming Li
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Ying Wang
- Department of Nuclear Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.,Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Wanting Niu
- Department of Orthopedics, Brigham and Women's Hospital, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Guoan Zhao
- School of Network Education, Beijing University of Posts and Telecommunications, Hebei, Beijing 100088, P.R. China
| | - Jithin K Raju
- Department of Clinical Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Jun Huo
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Bin Wu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Bo Yin
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yongsheng Song
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Renge Bu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
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31
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Geens M, Chuva De Sousa Lopes SM. X chromosome inactivation in human pluripotent stem cells as a model for human development: back to the drawing board? Hum Reprod Update 2018; 23:520-532. [PMID: 28582519 DOI: 10.1093/humupd/dmx015] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Accepted: 05/17/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Human pluripotent stem cells (hPSC), both embryonic and induced (hESC and hiPSC), are regarded as a valuable in vitro model for early human development. In order to fulfil this promise, it is important that these cells mimic as closely as possible the in vivo molecular events, both at the genetic and epigenetic level. One of the most important epigenetic events during early human development is X chromosome inactivation (XCI), the transcriptional silencing of one of the two X chromosomes in female cells. XCI is important for proper development and aberrant XCI has been linked to several pathologies. Recently, novel data obtained using high throughput single-cell technology during human preimplantation development have suggested that the XCI mechanism is substantially different from XCI in mouse. It has also been suggested that hPSC show higher complexity in XCI than the mouse. Here we compare the available recent data to understand whether XCI during human preimplantation can be properly recapitulated using hPSC. OBJECTIVE AND RATIONALE We will summarize what is known on the timing and mechanisms of XCI during human preimplantation development. We will compare this to the XCI patterns that are observed during hPSC derivation, culture and differentiation, and comment on the cause of the aberrant XCI patterns observed in hPSC. Finally, we will discuss the implications of the aberrant XCI patterns on the applicability of hPSC as an in vitro model for human development and as cell source for regenerative medicine. SEARCH METHODS Combinations of the following keywords were applied as search criteria in the PubMed database: X chromosome inactivation, preimplantation development, embryonic stem cells, induced pluripotent stem cells, primordial germ cells, differentiation. OUTCOMES Recent single-cell RNASeq data have shed new light on the XCI process during human preimplantation development. These indicate a gradual inactivation on both XX chromosomes, starting from Day 4 of development and followed by a random choice to inactivate one of them, instead of the mechanism in mice where imprinted XCI is followed by random XCI. We have put these new findings in perspective using previous data obtained in human (and mouse) embryos. In addition, there is an ongoing discussion whether or not hPSC lines show X chromosome reactivation upon derivation, mimicking the earliest embryonic cells, and the XCI states observed during culture of hPSC are highly variable. Recent studies have shown that hPSC rapidly progress to highly aberrant XCI patterns and that this process is probably driven by suboptimal culture conditions. Importantly, these aberrant XCI states seem to be inherited by the differentiated hPSC-progeny. WIDER IMPLICATIONS The aberrant XCI states (and epigenetic instability) observed in hPSC throw a shadow on their applicability as an in vitro model for development and disease modelling. Moreover, as the aberrant XCI states observed in hPSC seem to shift to a more malignant phenotype, this may also have important consequences for the safety aspect of using hPSC in the clinic.
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Affiliation(s)
- Mieke Geens
- Research Group Reproduction and Genetics, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Brussels, Belgium
| | - Susana M Chuva De Sousa Lopes
- Department of Anatomy and Embryology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.,Department of Reproductive Medicine, Ghent-Fertility and Stem Cell Team (G-FaST), Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium
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32
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Patterson B, Tanaka Y, Park IH. New Advances in Human X chromosome status from a Developmental and Stem Cell Biology. Tissue Eng Regen Med 2017; 14:643-652. [PMID: 29276809 PMCID: PMC5738034 DOI: 10.1007/s13770-017-0096-4] [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: 09/25/2017] [Revised: 10/16/2017] [Accepted: 11/03/2017] [Indexed: 11/26/2022] Open
Abstract
Recent advances in stem cell biology have dramatically increased the understanding of molecular and cellular mechanism of pluripotency and cell fate determination. Additionally, pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), arose as essential resources for disease modeling and cellular therapeutics. Despite these advancements, the epigenetic dysregulation in pluripotency such as the imprinting status, and X chromosome dosage compensation, and its consequences on future utility of PSCs yet remain unresolved. In this review, we will focus on the X chromosome regulation in human PSCs (hPSCs). We will introduce the previous findings in the dosage compensation process on mouse model, and make comparison with those of human systems. Particularly, the biallelic X chromosome activation status of human preimplantation embryos, and the regulation of the active X chromosome by human specific lincRNA, XACT, will be discussed. We will also discuss the recent findings on higher order X chromosome architecture utilizing Hi-C, and abnormal X chromosome status in hPSCs.
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Affiliation(s)
- Benjamin Patterson
- Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520 USA
| | - Yoshiaki Tanaka
- Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520 USA
| | - In-Hyun Park
- Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520 USA
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33
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Zacharopoulou E, Gazouli M, Tzouvala M, Vezakis A, Karamanolis G. The contribution of long non-coding RNAs in Inflammatory Bowel Diseases. Dig Liver Dis 2017; 49:1067-1072. [PMID: 28869157 DOI: 10.1016/j.dld.2017.08.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 07/23/2017] [Accepted: 08/01/2017] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) are multifactorial autoimmune diseases with growing prevalence but the interaction between genetic, environmental and immunologic factors in their development is complex and remains obscure. There is great need to understand their pathogenetic mechanisms and evolve diagnostic and therapeutic tools. Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are known to interfere in gene regulation but their roles and functions have not yet been fully understood. While they are widely investigated in cancers, little is known about their contribution in other diseases. There is growing evidence that lncRNAs play critical role in regulation of immune system and that they interfere in the pathogenetic mechanisms of autoimmune diseases, like IBDs. Recent studies have identified lncRNAs in the proximity of IBD-associated genes and single nucleotide polymorphisms within IBD-associated lncRNAs as well. Furthermore, blood samples and pinch biopsies were also analyzed and a plethora of lncRNAs are found to be deregulated in Crohn's disease (CD), Ulcerative colitis (UC) or both. (Especially in UC samples the lncRNAs INFG-AS1 and BC012900 were found to be significantly up-regulated. Similarly, ANRIL, a lncRNA that nest different disease associated SNPs, is significantly down-regulated in inflamed IBD tissue.) This review aims at recording for the first time recent data about lncRNAs found to be deregulated in IBDs and discussing suggestive pathogenetic mechanisms and future use of lncRNAs as biomarkers.
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Affiliation(s)
- Eirini Zacharopoulou
- Department of Gastroenterology, General Hospital of Nikea and Piraeus "Agios Panteleimon", Nikea, Greece.
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Tzouvala
- Department of Gastroenterology, General Hospital of Nikea and Piraeus "Agios Panteleimon", Nikea, Greece
| | - Antonios Vezakis
- 2nd Department of Surgery, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Karamanolis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School, Athens University, Athens, Greece
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Niu ZS, Niu XJ, Wang WH. Long non-coding RNAs in hepatocellular carcinoma: Potential roles and clinical implications. World J Gastroenterol 2017; 23:5860-5874. [PMID: 28932078 PMCID: PMC5583571 DOI: 10.3748/wjg.v23.i32.5860] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 05/10/2017] [Accepted: 07/22/2017] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are a subgroup of non-coding RNA transcripts greater than 200 nucleotides in length with little or no protein-coding potential. Emerging evidence indicates that lncRNAs may play important regulatory roles in the pathogenesis and progression of human cancers, including hepatocellular carcinoma (HCC). Certain lncRNAs may be used as diagnostic or prognostic markers for HCC, a serious malignancy with increasing morbidity and high mortality rates worldwide. Therefore, elucidating the functional roles of lncRNAs in tumors can contribute to a better understanding of the molecular mechanisms of HCC and may help in developing novel therapeutic targets. In this review, we summarize the recent progress regarding the functional roles of lncRNAs in HCC and explore their clinical implications as diagnostic or prognostic biomarkers and molecular therapeutic targets for HCC.
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MESH Headings
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinogenesis/genetics
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/mortality
- Disease Progression
- Early Detection of Cancer/methods
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Liver Neoplasms/diagnosis
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/mortality
- Molecular Targeted Therapy/methods
- Prognosis
- RNA, Long Noncoding/analysis
- RNA, Long Noncoding/antagonists & inhibitors
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Xiao-Jun Niu
- Oncology Specialty, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Medical Department of Qingdao University, Qingdao 266071, Shandong Province, China
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Acharya S, Hartmann M, Erhardt S. Chromatin-associated noncoding RNAs in development and inheritance. WILEY INTERDISCIPLINARY REVIEWS-RNA 2017; 8. [PMID: 28840663 DOI: 10.1002/wrna.1435] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 06/30/2017] [Accepted: 07/03/2017] [Indexed: 12/13/2022]
Abstract
Noncoding RNAs (ncRNAs) have emerged as crucial players in chromatin regulation. Their diversity allows them to partake in the regulation of numerous cellular processes across species. During development, long and short ncRNAs act in conjunction with each other where long ncRNAs (lncRNAs) are best understood in establishing appropriate gene expression patterns, while short ncRNAs (sRNAs) are known to establish constitutive heterochromatin and suppress mobile elements. Additionally, increasing evidence demonstrates roles of sRNAs in several typically lncRNA-mediated processes such as dosage compensation, indicating a complex regulatory network of noncoding RNAs. Together, various ncRNAs establish many mitotically heritable epigenetic marks during development. Additionally, they participate in mechanisms that regulate maintenance of these epigenetic marks during the lifespan of the organism. Interestingly, some epigenetic traits are transmitted to the next generation(s) via paramutations or transgenerational inheritance mediated by sRNAs. In this review, we give an overview of the various functions and regulations of ncRNAs and the mechanisms they employ in the establishment and maintenance of epigenetic marks and multi-generational transmission of epigenetic traits. WIREs RNA 2017, 8:e1435. doi: 10.1002/wrna.1435 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Sreemukta Acharya
- Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, and CellNetworks, Im Neuenheimer Feld 282, Heidelberg, Germany
| | - Mark Hartmann
- Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sylvia Erhardt
- Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, and CellNetworks, Im Neuenheimer Feld 282, Heidelberg, Germany
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36
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Balloy V, Koshy R, Perra L, Corvol H, Chignard M, Guillot L, Scaria V. Bronchial Epithelial Cells from Cystic Fibrosis Patients Express a Specific Long Non-coding RNA Signature upon Pseudomonas aeruginosa Infection. Front Cell Infect Microbiol 2017; 7:218. [PMID: 28611953 PMCID: PMC5447040 DOI: 10.3389/fcimb.2017.00218] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 05/11/2017] [Indexed: 01/09/2023] Open
Abstract
Pseudomonas aeruginosa (Pa) is the leading cause of chronic lung infection in Cystic Fibrosis (CF) patients. It is well recognized that CF epithelial cells fail to develop an appropriate response to infection, allowing bacterial colonization and a chronic inflammatory response. Since long non-coding RNAs (lncRNAs), are known to play a key role in regulating mammalian innate immune response, we hypothesized that CF cells exposed to Pa could express a specific lncRNA signature responsible of the maladaptative CF response. We analyzed transcriptomic datasets to compare the expression profiles of lncRNAs in primary CF and non-CF epithelial cells infected with Pa at 0, 2, 4, and 6 h of infection. Our analysis identified temporal expression signatures of 25, 73, 15, and 26 lncRNA transcripts differentially expressed at 0, 2, 4, and 6 h post-infection respectively, between CF and non-CF cells. In addition, we identified profiles specific to CF and non-CF cells. The differential expression of two candidate lncRNAs were independently validated using real-time PCR. We identified a specific CF signature of lncRNA expression in a context of Pa infection that could potentially play a role in the maladaptive immune response of CF patients.
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Affiliation(s)
- Viviane Balloy
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA)Paris, France
| | - Remya Koshy
- GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics and Integrative BiologyDelhi, India
| | - Lea Perra
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA)Paris, France
| | - Harriet Corvol
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA)Paris, France.,Pneumologie Pédiatrique, AP-HP, Hôpital TrousseauParis, France
| | - Michel Chignard
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA)Paris, France
| | - Loïc Guillot
- Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA)Paris, France
| | - Vinod Scaria
- GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics and Integrative BiologyDelhi, India.,CSIR Institute of Genomics and Integrative Biology, Academy of Scientific and Innovative ResearchDelhi, India
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37
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Affiliation(s)
- Chao-Po Lin
- Division of Cellular and Developmental Biology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94705
| | - Lin He
- Division of Cellular and Developmental Biology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94705
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38
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Yan Y, Xu Z, Li Z, Sun L, Gong Z. An Insight into the Increasing Role of LncRNAs in the Pathogenesis of Gliomas. Front Mol Neurosci 2017; 10:53. [PMID: 28293170 PMCID: PMC5328963 DOI: 10.3389/fnmol.2017.00053] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 02/15/2017] [Indexed: 02/05/2023] Open
Abstract
Long non-coding RNAs (LncRNAs) are essential epigenetic regulators with critical roles in tumor initiation and malignant progression. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of gliomas are not fully understood. With the development of deep sequencing analyses, an extensive amount of functional non-coding RNAs has been discovered in glioma tissues and cell lines. Additionally, the contributions of several lncRNAs, such as Hox transcript antisense intergenic RNA, H19 and Colorectal neoplasia differentially expressed, previously reported to be involved in other pathogenesis and processes to the oncogenesis of glioblastoma are currently addressed. Thus, lncRNAs detected in tumor tissues could serve as candidate diagnostic biomarkers and therapeutic targets for gliomas. To understand the potential function of lncRNAs in gliomas, in this review, we briefly describe the profile of lncRNAs in human glioma research and therapy. Then, we discuss the individual lncRNA that has been under intensive investigation in glioma research, and the focus is its mechanism and clinical implication.
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Affiliation(s)
- Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South UniversityChangsha, China
- Institute of Hospital Pharmacy, Central South UniversityChangsha, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South UniversityChangsha, China
| | - Zhi Li
- Center for Molecular Medicine, Xiangya Hospital, Key Laboratory of Molecular Radiation Oncology of Hunan Province, Central South UniversityChangsha, China
| | - Lunquan Sun
- Center for Molecular Medicine, Xiangya Hospital, Key Laboratory of Molecular Radiation Oncology of Hunan Province, Central South UniversityChangsha, China
| | - Zhicheng Gong
- Department of Pharmacy, Xiangya Hospital, Central South UniversityChangsha, China
- Institute of Hospital Pharmacy, Central South UniversityChangsha, China
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Deng LL, Chi YY, Liu L, Huang NS, Wang L, Wu J. LINC00978 predicts poor prognosis in breast cancer patients. Sci Rep 2016; 6:37936. [PMID: 27897214 PMCID: PMC5126584 DOI: 10.1038/srep37936] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 11/01/2016] [Indexed: 12/28/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs in the human genome that involves in breast cancer development and progression. Here, we identify a lncRNA, LINC00978, which is upregulated in breast cancer cell lines and tissues compared with corresponding controls. Furthermore, LINC00978 expression is negatively associated with hormone receptor (HR) status in 195 breast cancer patients studied (p = 0.033). Kaplan–Meier survival analysis shows that patients with high LINC00978 expression have poorer disease-free survival (DFS) than those with low LINC00978 expression (p = 0.012), and multivariate analysis identifies LINC00978 as an independent prognostic factor in breast cancer (p = 0.008, hazard ratio [HR] = 2.270, 95% confidence interval [CI] 1.237–4.165). Our study indicates that LINC00978 may be an oncogene in breast cancer, and can serve as a potential biomarker to predict prognosis in breast cancer patients.
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Affiliation(s)
- Lin-Lin Deng
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, 200032, China.,Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Ya-Yun Chi
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, 200032, China.,Department of Oncology, Fudan University, Shanghai Medical College, Shanghai, 200032, China
| | - Lei Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, 200032, China.,Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Nai-Si Huang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, 200032, China.,Department of Oncology, Fudan University, Shanghai Medical College, Shanghai, 200032, China
| | - Lin Wang
- Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Jiong Wu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, 200032, China.,Department of Oncology, Fudan University, Shanghai Medical College, Shanghai, 200032, China.,Collaborative Innovation Center for Cancer Medicine, China
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