Abstract
BackgroundIt is now obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long non-coding RNAs (lncRNAs). Many lncRNAs show aberrant expression in cancer, and some of them have been linked to cell transformation. However, the underlying mechanisms remain poorly understood and it is unknown how the sequences of lncRNA dictate their function.ResultsHere we characterize the function of the p53-regulated human lncRNA LINC-PINT in cancer. We find that LINC-PINT is downregulated in multiple types of cancer and acts as a tumor suppressor lncRNA by reducing the invasive phenotype of cancer cells. A cross-species analysis identifies a highly conserved sequence element in LINC-PINT that is essential for its function. This sequence mediates a specific interaction with PRC2, necessary for the LINC-PINT-dependent repression of a pro-invasion signature of genes regulated by the transcription factor EGR1.ConclusionsOur findings support a conserved functional co-dependence between LINC-PINT and PRC2 and lead us to propose a new mechanism where the lncRNA regulates the availability of free PRC2 at the proximity of co-regulated genomic loci.
Highlights
It is obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long non-coding RNAs
Polycomb Repressive Complex 2 (PRC2) catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), a mark of silent chromatin, and while PRC2 is essential for development, its deregulation leads to cancer progression
We found that LINCPINT acts as tumor suppressor Long non-coding RNA (lncRNA) that inhibits the migration capacity of cancer cells by repressing an invasion gene signature in a PRC2-dependent manner
Summary
It is obvious that the majority of cellular transcripts do not code for proteins, and a significant subset of them are long non-coding RNAs (lncRNAs). An important part of the non-coding genome is transcribed to produce non-coding RNAs, and a subset of them are long (>200 nt), capped, and polyadenylated transcripts transcribed by RNA polymerase II, collectively called long non-coding RNAs (lncRNAs) [2]. It is clear that many lncRNAs can regulate genome function and gene expression [3, 4]. Among the variety of mechanisms reported, a number of lncRNAs have been proposed to regulate gene expression in coordination with the Polycomb Repressive Complex 2 (PRC2) [14,15,16]. Multiple lncRNAs have been shown to interact with this chromatin complex, the significance of these findings is currently under active debate [20,21,22]
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