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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*

Author Affiliations

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

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

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

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

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

6 Stem 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

Published: 26 September 2013

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 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.

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.

Keywords:
lincRNA; non-coding RNA; p53; gene regulation; Polycomb repressive complex 2