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      Long non-coding RNA in stem cell pluripotency and lineage commitment: functions and evolutionary conservation

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          Abstract

          LncRNAs have recently emerged as new and fundamental transcriptional and post-transcriptional regulators acting at multiple levels of gene expression. Indeed, lncRNAs participate in a wide variety of stem cell and developmental processes, acting in cis and/or in trans in the nuclear and/or in the cytoplasmic compartments, and generating an intricate network of interactions with RNAs, enhancers, and chromatin-modifier complexes. Given the versatility of these molecules to operate in different subcellular compartments, via different modes of action and with different target specificity, the interest in this research field is rapidly growing. Here, we review recent progress in defining the functional role of lncRNAs in stem cell biology with a specific focus on the underlying mechanisms. We also discuss recent findings on a new family of evolutionary conserved lncRNAs transcribed from ultraconserved elements, which show perfect conservation between human, mouse, and rat genomes, and that are emerging as new player in this complex scenario.

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          Most cited references71

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          The transcriptional landscape of the mammalian genome.

          This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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            Long noncoding RNA as modular scaffold of histone modification complexes.

            Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
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              Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells.

              The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome, resulting in altered patterns of gene expression. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) that occurs upon derivation of human iPSCs and identify numerous lincRNAs whose expression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression was elevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote the emergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of key pluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found that one such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration for critical functions of lincRNAs in the derivation of pluripotent stem cells.
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                Author and article information

                Contributors
                +39 081-6132718 , annalisa.fico@igb.cnr.it
                Journal
                Cell Mol Life Sci
                Cell. Mol. Life Sci
                Cellular and Molecular Life Sciences
                Springer International Publishing (Cham )
                1420-682X
                1420-9071
                3 January 2019
                3 January 2019
                2019
                : 76
                : 8
                : 1459-1471
                Affiliations
                [1 ]ISNI 0000 0001 1940 4177, GRID grid.5326.2, Stem Cell Fate Laboratory, , Institute of Genetics and Biophysics “A. Buzzati-Traverso”, CNR, ; 80131 Naples, Italy
                [2 ]ISNI 0000 0001 1940 4177, GRID grid.5326.2, Institute of Genetics and Biophysics “A. Buzzati-Traverso”, CNR, ; 80131 Naples, Italy
                [3 ]ISNI 0000 0001 0930 2361, GRID grid.4514.4, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, , Lund University, ; 22184 Lund, Sweden
                Author information
                http://orcid.org/0000-0003-2374-585X
                Article
                3000
                10.1007/s00018-018-3000-z
                6439142
                30607432
                3092b06a-2dcc-434e-ace7-21297e850e12
                © The Author(s) 2019

                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.

                History
                : 3 October 2018
                : 13 November 2018
                : 17 December 2018
                Categories
                Review
                Custom metadata
                © Springer Nature Switzerland AG 2019

                Molecular biology
                embryonic stem cells,lncrnas,ultraconserved elements,t-uces
                Molecular biology
                embryonic stem cells, lncrnas, ultraconserved elements, t-uces

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