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Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein-coding RNAs

Jörg Hackermüller123*, Kristin Reiche123, Christian Otto45, Nadine Hösler56, Conny Blumert67, Katja Brocke-Heidrich6, Levin Böhlig8, Anne Nitsche4, Katharina Kasack356, Peter Ahnert59, Wolfgang Krupp10, Kurt Engeland8, Peter F Stadler11121334 and Friedemann Horn67

Author Affiliations

1 Young Investigators Group Bioinformatics and Transcriptomics, Department Proteomics, Helmholtz Centre for Environmental Research – UFZ, Leipzig, Germany

2 Department for Computer Science, University of Leipzig, Leipzig, Germany

3 RNomics Group, Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology – IZI, Leipzig, Germany

4 Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany

5 LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany

6 Institute of Clinical Immunology, University of Leipzig, Leipzig, Germany

7 Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology – IZI, Leipzig, Germany

8 Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany

9 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

10 Clinic of Neurosurgery, University of Leipzig, Leipzig, Germany

11 Max-Planck Institute for Mathematics in the Sciences, Leipzig, Germany

12 Santa Fe Institute, Santa Fe, NM, USA

13 Department of Theoretical Chemistry, University of Vienna, Vienna, Austria

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Genome Biology 2014, 15:R48  doi:10.1186/gb-2014-15-3-r48

Published: 4 March 2014

Abstract

Background

The genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein-coding RNAs. Despite increasing numbers of functional reports of individual long non-coding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein-coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental in the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identified lncRNAs expressed differentially in response to oncologically relevant processes and cell-cycle, p53 and STAT3 pathways, using tiling arrays.

Results

We found that up to 80% of the pathway-triggered transcriptional responses are non-coding. Among these we identified very large macroRNAs with pathway-specific expression patterns and demonstrated that these are likely continuous transcripts. MacroRNAs contain elements conserved in mammals and sauropsids, which in part exhibit conserved RNA secondary structure. Comparing evolutionary rates of a macroRNA to adjacent protein-coding genes suggests a local action of the transcript. Finally, in different grades of astrocytoma, a tumor disease unrelated to the initially used cell lines, macroRNAs are differentially expressed.

Conclusions

It has been shown previously that the majority of expressed non-ribosomal transcripts are non-coding. We now conclude that differential expression triggered by signaling pathways gives rise to a similar abundance of non-coding content. It is thus unlikely that the prevalence of non-coding transcripts in the cell is a trivial consequence of leaky or random transcription events.