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Genome Biol. 2018 Mar 15;19(1):32. doi: 10.1186/s13059-018-1405-5.

Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci.

Author information

1
The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
2
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
3
Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK.
4
Present address: The Milner Therapeutics Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
5
Present address: MRC Prion Unit, UCL Institute of Neurology, Queen Square House, Queen Square, London, WC1N 3BG, UK.
6
Centro de Genómica y Bioinformática, Facultad de Ciencias, Universidad Mayor, Santiago, Chile.
7
University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Miami, FL, 33136, USA.
8
Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
9
School of Pharmaceutical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 580, São Paulo, 05508, Brazil.
10
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
11
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
12
The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK. t.kouzarides@gurdon.cam.ac.uk.

Abstract

BACKGROUND:

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 promoter conservation and positional conservation as indicators of functional commonality.

RESULTS:

We identify 665 conserved lncRNA promoters in mouse and human that are preserved in genomic position relative to orthologous coding genes. These positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are coexpressed in a tissue-specific manner. Over half of positionally conserved RNAs in this set are linked to chromatin organization structures, overlapping binding sites for the CTCF chromatin organiser and located at chromatin loop anchor points and borders of topologically associating domains (TADs). We define these RNAs as topological anchor point RNAs (tapRNAs). 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. Furthermore, we find that tapRNAs contain conserved sequence domains that are enriched in motifs for zinc finger domain-containing RNA-binding proteins and transcription factors, whose binding sites are found mutated in cancers.

CONCLUSIONS:

This work leverages positional conservation to identify lncRNAs with potential importance in genome organization, development and disease. The evidence that many developmental transcription factors are physically and functionally connected to lncRNAs represents an exciting stepping-stone to further our understanding of genome regulation.

KEYWORDS:

Cancer; Chromatin architecture; Development; Topology; Zinc finger; lncRNAs

PMID:
29540241
PMCID:
PMC5853149
DOI:
10.1186/s13059-018-1405-5
[Indexed for MEDLINE]
Free PMC Article

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