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

Oskar Marín-Béjar¹, Francesco P Marchese¹, Alejandro Athie¹, Yolanda Sánchez¹,Jovanna González¹, Victor Segura¹, Lulu Huang², Isabel Moreno³, Alfons Navarro⁴,Mariano Monzó⁴, Jesús García-Foncillas⁵, John L Rinn⁶, Shuling Guo² and Maite Huarte¹^*

*Corresponding author: Maite Huarte maitehuarte@unav.es

Author Affiliations

¹Center for Applied Medical Research, University of Navarra, 55 Pio XII Avenue., 31008 Pamplona, Spain

²Department of Antisense Drug Discovery, Isis Pharmaceuticals, 2855 Gazelle Court., Carlsbad, CA 92008, USA

³Department of Medical Oncology, Hospital Municipal de Badalona, 9-13 Via Augusta Street, 08911 Badalona, Spain

⁴Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, University of Barcelona Medical School, IDIBAPS, 143 Casanova Street, 080360 Barcelona, Spain

⁵Department of Oncology, Translational Oncology Division, Health Research Institute Fundación Jiménez Díaz University Hospital, Autonomous University of Madrid, 2 Reyes Catolicos Avenue, 28040 Madrid, Spain

⁶Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA

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Genome Biology 2013, 14:R104 doi:10.1186/gb-2013-14-9-r104

The electronic version of this article is the complete one and can be found online at:http://genomebiology.com/2013/14/9/R104

Received:	24 April 2013
Revisions received:	11 July 2013
Accepted:	26 September 2013
Published:	26 September 2013

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The 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.

Results

Here we characterize a lincRNA named Pint (p53 induced noncoding transcript). We show that Pintis 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.

Conclusions

Our 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.