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      Gas5 is an essential lncRNA regulator for self-renewal and pluripotency of mouse embryonic stem cells and induced pluripotent stem cells

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          Abstract

          Background

          The regulatory role of long noncoding RNAs (lncRNAs) have been partially proved in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).

          Methods

          In the current study, we investigated mouse ESC (mESC) self-renewal, differentiation, and proliferation in vitro by knocking down a lncRNA, growth arrest specific 5 (Gas5). A series of related indicators were examined by cell counting kit-8 (CCK-8) assay, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), Western blot, alkaline phosphatase staining, propidium iodide (PI) staining, Annexin V staining, competition growth assay, immunofluorescence, and chromatin immunoprecipitation (ChIP)-qPCR. An in vivo teratoma formation assay was also performed to validate the in vitro results. qRT-PCR, fluorescence-activated cell sorting (FACS), alkaline phosphatase staining, and immunofluorescence were used to evaluate the role of Gas5 during mouse iPSC reprogramming. The regulatory axis of Dicer-miR291a–cMyc-Gas5 and the relationship between Gas5 and Tet/5hmC in mESCs was examined by qRT-PCR, Dot blot, and Western blot.

          Results

          We identified that Gas5 was required for self-renewal and pluripotency of mESCs and iPSCs. Gas5 formed a positive feedback network with a group of key pluripotent modulators (Sox2, Oct4, Nanog, Tcl1, Esrrb, and Tet1) in mESCs. Knockdown of Gas5 promoted endodermal differentiation of mESCs and impaired the efficiency of iPSC reprogramming. In addition, Gas5 was regulated by the Dicer-miR291a–cMyc axis and was involved in the DNA demethylation process in mESCs.

          Conclusions

          Taken together, our results suggest that the lncRNA Gas5 plays an important role in modulating self-renewal and pluripotency of mESCs as well as iPSC reprogramming.

          Electronic supplementary material

          The online version of this article (10.1186/s13287-018-0813-5) contains supplementary material, which is available to authorized users.

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          Braveheart, a long noncoding RNA required for cardiovascular lineage commitment.

          Carla A Klattenhoff, Johanna C. Scheuermann, Lauren Surface … (2013)
          Long noncoding RNAs (lncRNAs) are often expressed in a development-specific manner, yet little is known about their roles in lineage commitment. Here, we identified Braveheart (Bvht), a heart-associated lncRNA in mouse. Using multiple embryonic stem cell (ESC) differentiation strategies, we show that Bvht is required for progression of nascent mesoderm toward a cardiac fate. We find that Bvht is necessary for activation of a core cardiovascular gene network and functions upstream of mesoderm posterior 1 (MesP1), a master regulator of a common multipotent cardiovascular progenitor. We also show that Bvht interacts with SUZ12, a component of polycomb-repressive complex 2 (PRC2), during cardiomyocyte differentiation, suggesting that Bvht mediates epigenetic regulation of cardiac commitment. Finally, we demonstrate a role for Bvht in maintaining cardiac fate in neonatal cardiomyocytes. Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development. Copyright © 2013 Elsevier Inc. All rights reserved.
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            GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer.

            M. Mourtada-Maarabouni, M Pickard, V. L. Hedge … (2009)
            Effective control of both cell survival and cell proliferation is critical to the prevention of oncogenesis and to successful cancer therapy. Using functional expression cloning, we have identified GAS5 (growth arrest-specific transcript 5) as critical to the control of mammalian apoptosis and cell population growth. GAS5 transcripts are subject to complex post-transcriptional processing and some, but not all, GAS5 transcripts sensitize mammalian cells to apoptosis inducers. We have found that, in some cell lines, GAS5 expression induces growth arrest and apoptosis independently of other stimuli. GAS5 transcript levels were significantly reduced in breast cancer samples relative to adjacent unaffected normal breast epithelial tissues. The GAS5 gene has no significant protein-coding potential but expression encodes small nucleolar RNAs (snoRNAs) in its introns. Taken together with the recent demonstration of tumor suppressor characteristics in the related snoRNA U50, our observations suggest that such snoRNAs form a novel family of genes controlling oncogenesis and sensitivity to therapy in cancer.
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              Long noncoding RNAs in cell-fate programming and reprogramming.

              Ryan Flynn, Howard Y. Chang (2014)
              In recent years, long noncoding RNAs (lncRNAs) have emerged as an important class of regulators of gene expression. lncRNAs exhibit several distinctive features that confer unique regulatory functions, including exquisite cell- and tissue-specific expression and the capacity to transduce higher-order spatial information. Here we review evidence showing that lncRNAs exert critical functions in adult tissue stem cells, including skin, brain, and muscle, as well as in developmental patterning and pluripotency. We highlight new approaches for ascribing lncRNA functions and discuss mammalian dosage compensation as a classic example of an lncRNA network coupled to stem cell differentiation.
              Article 0 comments Cited 278 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jiajie Tu:
                ORCID: http://orcid.org/0000-0002-3895-3726
                +86-0551-65161206 , tujiajie@ahmu.edu.cn
                Geng Tian: gengtian_99@yahoo.com
                Hoi-Hung Cheung: b122528@mailserv.cuhk.edu.hk
                Wei Wei: +86-0551-65161209 , wwei22@ahmu.edu.cn
                Tin-lap Lee: +852-39434436 , leetl@cuhk.edu.hk
                Journal
                Journal ID (nlm-ta): Stem Cell Res Ther
                Journal ID (iso-abbrev): Stem Cell Res Ther
                Title: Stem Cell Research & Therapy
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1757-6512
                Publication date (Electronic): 21 March 2018
                Publication date PMC-release: 21 March 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 71
                Affiliations
                [1 ]ISNI 0000 0000 9490 772X, GRID grid.186775.a, Institute of Clinical Pharmacology, Key Laboratory of Anti-inflammatory and Immune Medicine, , Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Anhui Medical University, ; 81# Meishan Road, Hefei, Anhui China
                [2 ]ISNI 0000 0004 1937 0482, GRID grid.10784.3a, Faculty of Medicine, School of Biomedical Sciences, , The Chinese University of Hong Kong, ; Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, N.T 622A Hong Kong, Special Administrative Region of China
                Author information
                http://orcid.org/0000-0002-3895-3726
                Article
                Publisher ID: 813
                DOI: 10.1186/s13287-018-0813-5
                PMC ID: 5863440
                PubMed ID: 29562912
                SO-VID: 607420f2-f6da-4e6b-9e5f-657ce07480f2
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 22 January 2018
                Date revision received : 20 February 2018
                Date accepted : 21 February 2018
                Funding
                Funded by: Natural Science Foundation of Anhui Province for young scholars
                Award ID: 1708085QH200
                Award Recipient :
                Funded by: Grants for Scientific Research of BSKY from Anhui Medical University
                Award ID: 4501041101
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Molecular medicine
                Keywords: lncrna,gas5,mescs,ipscs,self-renewal,pluripotency
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: lncrna, gas5, mescs, ipscs, self-renewal, pluripotency

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