'Linc-Ing' a Noncoding RNA to a Central Cellular Pathway
ScienceDaily (Aug. 12, 2010) — The recent discovery of more than a thousand genes known as large intergenic non-coding RNAs (or "lincRNAs") opened up a new approach to understanding the function and organization of the genome. That surprising breakthrough is now made even more compelling with the finding that dozens of these lincRNAs are induced by p53 (the most commonly mutated gene in cancer), suggesting that this class of genes plays a critical role in cell development and regulation. Furthermore, the researchers identify one lincRNA in particular (lincRNA-p21), and demonstrate its critical role in suppressing the reading of many genes across the genome following p53 activation.
Led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and the Broad Institute, the results are published in the August 6 issue of the journal Cell, which appears online July 29.
"We think that lincRNA-p21 may represent a new class of 'tumor suppressor lincRNAs,'" said senior author John Rinn, PhD, Assistant Professor of Pathology at BIDMC and Harvard Medical School, and an Associate Member of the Broad Institute. "These findings may lead to the identification of novel biomarkers and targets for anti-cancer therapies, as well as add to our understanding of the mechanisms of gene regulation by lincRNAs."
Since the central role of the p53 gene in cancer was first described more than 30 years ago, literally thousands of scientific publications have been published describing various aspects of its "tumor suppressor" role in regulating cell cycle and cell death (apoptosis) in response to DNA damage, by turning various relevant response genes on or off. However, the intermediary partners and mechanisms by which it carries out its function are still little understood. This current work demonstrates that several dozen lincRNAs are targeted directly by p53, and lincRNA-p21 in particular responds to p53 signaling by suppressing multiple genes across the genome to drive apoptosis.
"We were surprised to find that lincRNA-p21 appears to be functioning as a global repressor, regulating hundreds of genes in the p53 pathway," said Maite Huarte, PhD, first and co-corresponding author."This lincRNA is playing defense for p53 to block other pathways in their efforts to interfere with p53's critical job of tumor suppression by cell death."
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Cell, Volume 142, Issue 3, 409-419, 29 July 2010
doi:10.1016/j.cell.2010.06.040
A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response
Maite Huarte1, 2, , , Mitchell Guttman1, 3, David Feldser3, 4, Manuel Garber1, Magdalena J. Koziol1, 2, Daniela Kenzelmann-Broz5, 6, Ahmad M. Khalil1, 2, Or Zuk1, Ido Amit1, Michal Rabani1, Laura D. Attardi5, 6, Aviv Regev1, 3, Eric S. Lander1, 3, 7, Tyler Jacks3, 4 and John L. Rinn1, 2, ,
1 The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
2 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
3 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
4 The Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA
5 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
6 Department of and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
7 Department of Systems Biology, Harvard Medical School, Boston, MA 02114, USA
Corresponding author
Corresponding author
Highlights► Several lincRNAs are regulated by p53 ► LincRNA-p21 is a bona fide p53 transcriptional target ► LincRNA-p21 mediates global gene repression and apoptosis in the p53 pathway ► LincRNA-p21 represses gene targets through physical association with hnRNP-K
Summary
Recently, more than 1000 large intergenic noncoding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediates apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulate their localization to sets of previously active genes.
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