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Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci

View ORCID ProfilePaulo P. Amaral, Tommaso Leonardi, Namshik Han, Emmanuelle Viré, Dennis K. Gascoigne, Raúl Arias-Carrasco, Magdalena Büscher, Anda Zhang, Stefano Pluchino, Vinicius Maracaja-Coutinho, Helder I. Nakaya, Martin Hemberg, Ramin Shiekhattar, Anton J. Enright, Tony Kouzarides
doi: https://doi.org/10.1101/051052
Paulo P. Amaral
1The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
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  • ORCID record for Paulo P. Amaral
Tommaso Leonardi
2EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK.
3Department of Clinical Neurosciences; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Clifford Allbutt Building-Cambridge Biosciences Campus, Hills Road, Cambridge, CB2 0PY, UK.
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Namshik Han
1The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
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Emmanuelle Viré
1The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
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Dennis K. Gascoigne
1The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
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Raúl Arias-Carrasco
4Centro de Genómica y Bioinformática, Facultad de Ciencias, Universidad Mayor, Camino La Pirámide 5750, Huechuraba, Santiago, 8580000, Chile
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Magdalena Büscher
1The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
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Anda Zhang
5University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Miami, FL 33136, USA.
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Stefano Pluchino
3Department of Clinical Neurosciences; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Clifford Allbutt Building-Cambridge Biosciences Campus, Hills Road, Cambridge, CB2 0PY, UK.
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Vinicius Maracaja-Coutinho
4Centro de Genómica y Bioinformática, Facultad de Ciencias, Universidad Mayor, Camino La Pirámide 5750, Huechuraba, Santiago, 8580000, Chile
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Helder I. Nakaya
6School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, São Paulo 05508, Brazil.
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Martin Hemberg
1The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
7Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
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Ramin Shiekhattar
5University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Miami, FL 33136, USA.
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Anton J. Enright
2EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK.
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Tony Kouzarides
1The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
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  • For correspondence: t.kouzarides@gurdon.cam.ac.uk
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Abstract

The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider positional conservation across mammalian genomes as an indicator of functional commonality. We identify 665 conserved lncRNA promoters in mouse and human genomes that are preserved in genomic position relative to orthologous coding genes. The identified ‘positionally conserved’ lncRNA genes are primarily associated with developmental transcription factor loci with which they are co-expressed in a tissue-specific manner. Strikingly, over half of all positionally conserved RNAs in this set are linked to distinct chromatin organization structures, overlapping the binding sites for the CTCF chromatin organizer and located at chromatin loop anchor points and borders of topologically associating domains (TADs). These topological anchor point (tap)RNAs possess conserved sequence domains that are enriched in potential recognition motifs for Zinc Finger proteins. Characterization of these noncoding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other’s expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Thus, interrogation of positionally conserved lncRNAs identifies a new subset of tapRNAs with shared functional properties. These results provide a large dataset of lncRNAs that conform to the “extended gene” model, in which conserved developmental genes are genomically and functionally linked to regulatory lncRNA loci across mammalian evolution.

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Posted May 04, 2016.
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Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci
Paulo P. Amaral, Tommaso Leonardi, Namshik Han, Emmanuelle Viré, Dennis K. Gascoigne, Raúl Arias-Carrasco, Magdalena Büscher, Anda Zhang, Stefano Pluchino, Vinicius Maracaja-Coutinho, Helder I. Nakaya, Martin Hemberg, Ramin Shiekhattar, Anton J. Enright, Tony Kouzarides
bioRxiv 051052; doi: https://doi.org/10.1101/051052
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Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci
Paulo P. Amaral, Tommaso Leonardi, Namshik Han, Emmanuelle Viré, Dennis K. Gascoigne, Raúl Arias-Carrasco, Magdalena Büscher, Anda Zhang, Stefano Pluchino, Vinicius Maracaja-Coutinho, Helder I. Nakaya, Martin Hemberg, Ramin Shiekhattar, Anton J. Enright, Tony Kouzarides
bioRxiv 051052; doi: https://doi.org/10.1101/051052

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