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Marz M.,University of Marburg | Gruber A.R.,University of Vienna | Gruber A.R.,Swiss Institute of Bioinformatics | Honer Zu Siederdissen C.,University of Vienna | And 17 more authors.
RNA Biology | Year: 2011

The overwhelming majority of small nucleolar RNAs (snoRNAs) fall into two clearly defined classes characterized by distinctive secondary structures and sequence motifs. A small group of diverse ncRNAs, however, shares the hallmarks of one or both classes of snoRNAs but differs substantially from the norm in some respects. Here, we compile the available information on these exceptional cases, conduct a thorough homology search throughout the available metazoan genomes, provide improved and expanded alignments, and investigate the evolutionary histories of these ncRNA families as well as their mutual relationships. © 2011 Landes Bioscience. Source


Ounzain S.,University of Lausanne | Pezzuto I.,University of Lausanne | Micheletti R.,University of Lausanne | Burdet F.,Swiss Institute of Bioinformatics | And 11 more authors.
Journal of molecular and cellular cardiology | Year: 2014

The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs. Copyright © 2014. Published by Elsevier Ltd. Source


Ng S.-Y.,Genome Institute of Singapore | Ng S.-Y.,National University of Singapore | Johnson R.,Bioinformatics and Genomics Group | Stanton L.W.,Genome Institute of Singapore | Stanton L.W.,National University of Singapore
EMBO Journal | Year: 2012

Long non-coding RNAs (lncRNAs) are a numerous class of newly discovered genes in the human genome, which have been proposed to be key regulators of biological processes, including stem cell pluripotency and neurogenesis. However, at present very little functional characterization of lncRNAs in human differentiation has been carried out. In the present study, we address this using human embryonic stem cells (hESCs) as a paradigm for pluripotency and neuronal differentiation. With a newly developed method, hESCs were robustly and efficiently differentiated into neurons, and we profiled the expression of thousands of lncRNAs using a custom-designed microarray. Some hESC-specific lncRNAs involved in pluripotency maintenance were identified, and shown to physically interact with SOX2, and PRC2 complex component, SUZ12. Using a similar approach, we identified lncRNAs required for neurogenesis. Knockdown studies indicated that loss of any of these lncRNAs blocked neurogenesis, and immunoprecipitation studies revealed physical association with REST and SUZ12. This study indicates that lncRNAs are important regulators of pluripotency and neurogenesis, and represents important evidence for an indispensable role of lncRNAs in human brain development. © 2012 European Molecular Biology Organization | All Rights Reserved. Source


Yu H.-B.,Genome Institute of Singapore | Yu H.-B.,National University of Singapore | Johnson R.,Genome Institute of Singapore | Johnson R.,Bioinformatics and Genomics Group | And 3 more authors.
Genome Research | Year: 2011

The differentiation of pluripotent embryonic stem cells is regulated by networks of activating and repressing transcription factors that orchestrate determinate patterns of gene expression. With the recent mapping of target sites for many transcription factors, it has been a conundrum that so few of the genes directly targeted by these factors are transcriptionally responsive to the binding of that factor. To address this, we generated genome-wide maps of the transcriptional repressor REST and five of its corepressors in mouse embryonic stem cells. Combining these binding-site maps with comprehensive gene-expression profiling, we show that REST is functionally heterogeneous. Approximately half of its binding sites apparently are nonfunctional, having weaker binding of REST and low recruitment of corepressors. In contrast, the other sites strongly recruit REST and corepressor complexes with varying numbers of components. Strikingly, the latter sites account for almost all observed gene regulation. These data support a model where productive gene repression by REST requires assembly of a multimeric "repressosome" complex, whereas weak recruitment of REST and its cofactors is insufficient to repress gene expression. © 2011 by Cold Spring Harbor Laboratory Press. Source


Ounzain S.,University of Lausanne | Pezzuto I.,University of Lausanne | Micheletti R.,University of Lausanne | Burdet F.,Swiss Institute of Bioinformatics | And 14 more authors.
Current Therapeutic Research - Clinical and Experimental | Year: 2014

The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs. •Fetal cardiac enhancers are transcribed, generating enhancer-derived lncRNAs. © 2014 . Source

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