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

Abstract

BackgroundThe 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.ResultsHere 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.ConclusionsThese 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.

Mammalian Endogenous Retroviruses

“…ERVs and other TEs can promote expression of RNAs antisense to coding genes (Fig. 3C) (130) and a number of more-recent studies indicate that ERV LTRs are overrepresented as a source of transcriptional promoters for lncRNAs (186,187,188). Although many such RNAs could simply be the result of "transcriptional noise" and have no function, regulatory roles for some specific cases are being revealed.…”

CAGE profiling of ncRNAs in hepatocellular carcinoma reveals widespread activation of retroviral LTR promoters in virus-induced tumors

“…We have recently shown that LTRs are massively transcribed in embryonic stem cells and iPS cells, some of which are involved in the maintenance of pluripotency (Fort et al 2014). Other studies demonstrated a high activity of distinct LTR subfamilies in stem cells using several different methods, including RNA-seq (Kelley and Rinn 2012;St Laurent et al 2013), DNase-seq (Jacques et al 2013), and MeDIP-seq (Xie et al 2013). Furthermore, an appropriate activation of LTRs is essential for iPS reprogramming (Lu et al 2014;Ohnuki et al 2014), suggesting that the expression of LTRs might be associated with cancerous features, such as poor differentiation and high proliferation potency.…”

Long noncoding RNAs as Organizers of Nuclear Architecture

“…One interesting direction is to explore their potential involvement in nuclear architecture under various physiological or pathological conditions. For example, the lncRNA VAD, which belongs to the recently discovered very long intergenic ncRNAs (vlincRNAs) (St Laurent et al, 2013), is required to maintain oncogene-induced senescence (Lazorthes et al, 2015). VAD activates the master gene INK4 in trans, presumably by promoting the removal of repressive H2A.Z at this locus (Lazorthes et al, 2015).…”