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VlincRNAs controlled by retroviral elements are a hallmark of pluripotency and cancer

Georges St Laurent12*, Dmitry Shtokalo13, Biao Dong4, Michael R Tackett1, Xiaoxuan Fan4, Sandra Lazorthes56, Estelle Nicolas56, Nianli Sang7, Timothy J Triche8, Timothy A McCaffrey9, Weidong Xiao4* and Philipp Kapranov1*

Author affiliations

1 St. Laurent Institute, One Kendall Square, Cambridge, MA

2 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI

3 A.P.Ershov Institute of Informatics Systems SB RAS, 6, Acad. Lavrentjev ave., Novosibirsk 630090, Russia

4 Department of Microbiology and Immunology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA

5 Université de Toulouse, UPS, LBCMCP, F-31062 Toulouse, France

6 CNRS, LBCMCP, F-31062 Toulouse, France

7 Department of Biology, Drexel University, 3245 Chestnut St, PISB 417, Philadelphia, PA

8 Department of Pathology, University of Southern California, 1975 Zonal Avenue, Los Angeles, CA

9 The George Washington University Medical Center, Department of Medicine, Division of Genomic Medicine, 2300 I St. NW, Washington, D.C

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Citation and License

Genome Biology 2013, 14:R73  doi:10.1186/gb-2013-14-7-r73

Published: 22 July 2013

Abstract

Background

The function of the non-coding portion of the human genome remains one of the most important questions of our time. Its vast complexity is exemplified by the recent identification of an unusual and notable component of the transcriptome - very long intergenic non-coding RNAs, termed vlincRNAs.

Results

Here we identify 2,147 vlincRNAs covering 10 percent of our genome. We show they are present not only in cancerous cells, but also in primary cells and normal human tissues, and are controlled by canonical promoters. Furthermore, vlincRNA promoters frequently originate from within endogenous retroviral sequences. Strikingly, the number of vlincRNAs expressed from endogenous retroviral promoters strongly correlates with pluripotency or the degree of malignant transformation. These results suggest a previously unknown connection between the pluripotent state and cancer via retroviral repeat-driven expression of vlincRNAs. Finally, we show that vlincRNAs can be syntenically conserved in humans and mouse and their depletion using RNAi can cause apoptosis in cancerous cells.

Conclusions

These intriguing observations suggest that vlincRNAs could create a framework that combines many existing short ESTs and lincRNAs into a landscape of very long transcripts functioning in the regulation of gene expression in the nucleus. Certain types of vlincRNAs participate at specific stages of normal development and, based on analysis of a limited set of cancerous and primary cell lines, they appear to be co-opted by cancer-associated transcriptional programs. This provides additional understanding of transcriptome regulation during the malignant state, and could lead to additional targets and options for its reversal.

Keywords:
vlincRNA; LTR; macroRNA; cancer; embryonic stem cell; non-coding RNA; intelligent scaffold; single molecule sequencing; RNAseq