Pint lincRNA connects the p53 pathway with epigenetic silencing by the Polycomb repressive complex 2

Abstract

BackgroundThe p53 transcription factor is located at the core of a complex wiring of signaling pathways that are critical for the preservation of cellular homeostasis. Only recently it has become clear that p53 regulates the expression of several long intergenic noncoding RNAs (lincRNAs). However, relatively little is known about the role that lincRNAs play in this pathway.ResultsHere we characterize a lincRNA named Pint (p53 induced noncoding transcript). We show that Pint is a ubiquitously expressed lincRNA that is finely regulated by p53. In mouse cells, Pint promotes cell proliferation and survival by regulating the expression of genes of the TGF-β, MAPK and p53 pathways. Pint is a nuclear lincRNA that directly interacts with the Polycomb repressive complex 2 (PRC2), and is required for PRC2 targeting of specific genes for H3K27 tri-methylation and repression. Furthermore, Pint functional activity is highly dependent on PRC2 expression. We have also identified Pint human ortholog (PINT), which presents suggestive analogies with the murine lincRNA. PINT is similarly regulated by p53, and its expression significantly correlates with the same cellular pathways as the mouse ortholog, including the p53 pathway. Interestingly, PINT is downregulated in colon primary tumors, while its overexpression inhibits the proliferation of tumor cells, suggesting a possible role as tumor suppressor.ConclusionsOur results reveal a p53 autoregulatory negative mechanism where a lincRNA connects p53 activation with epigenetic silencing by PRC2. Additionally, we show analogies and differences between the murine and human orthologs, identifying a novel tumor suppressor candidate lincRNA.

Missing Links in Epithelial-Mesenchymal Transition: Long Non-Coding RNAs Enter the Arena

“…Takahashi et al demonstrated that PVT1 knockdown could upregulate Smad4 and apoptosisassociated genes related to the TGF-β pathway [119]. Marin-Bejar et al revealed that PINT could promote cell proliferation and survival by regulating the expression of genes of the TGF-β, MAPK and p53 pathways in mouse cells [120]. Linc00974 was reported to be involved in a Linc00974-miR-642-KRT19-TGF-β signaling pathway [121].…”

The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2

“…In addition to HOTAIR, Xist, RepA, Kcnq1ot1, and Braveheart, as described above, additional PRC2 target transcripts now included the lncRNAs MALAT1 (Guil et al 2012), both sense and antisense transcripts of H19 (Zhao et al 2010), ANRIL (Kotake et al 2011), MEG3 (Zhao et al 2010;Kaneko et al 2014a), PINC (Shore et al 2012), both sense and antisense transcripts of Nespas (Zhao et al 2010), NEAT1 (Guttman et al 2011), Air (Zhao et al 2010), Pint (Marin-Béjar et al 2013), lncRNA-EBIC ), BLACAT1/linc-UBC1 (which was suggested to act in trans) (He et al 2013), and COLDAIR from Arabidopsis thaliana (Heo and Sung 2011).…”

Long non-coding RNAs and chromatin modifiers

“…UBC1 PRC2 RiP-qPCR (antibodies α-eZH2, and α-Suz12) 47 Pint PRC2 RiP-qPCR (antibody α-Suz12), in vitro transcribed biotinylated RNA pull-down with cell extracts or purified PRC2 48 or absence of interaction correlates with lineage-specific differences observed for these chromatin modifications in the Kcnq1 locus. 35 Interestingly, the genes regulated in cis by Kcnq1ot1, which are imprinted both in the embryo and in the placenta of the paternal chromosome, are located closer to the promoter, while the genes repressed only in the placenta are those located more distally from the promoter.…”