Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms

Autor: Hestia Mellert, Justin A. Freeman, Robin D. Dowell, Joaquín M. Espinosa, Matthew D. Galbraith, Veronica L. Dengler, Xin Luo, Mary A. Allen, Zdenek Andrysik, W. Lee Kraus, Kelly D. Sullivan, Anna L. Guarnieri
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: eLife, Vol 3 (2014)
eLife
Popis: The p53 transcription factor is a potent suppressor of tumor growth. We report here an analysis of its direct transcriptional program using Global Run-On sequencing (GRO-seq). Shortly after MDM2 inhibition by Nutlin-3, low levels of p53 rapidly activate ∼200 genes, most of them not previously established as direct targets. This immediate response involves all canonical p53 effector pathways, including apoptosis. Comparative global analysis of RNA synthesis vs steady state levels revealed that microarray profiling fails to identify low abundance transcripts directly activated by p53. Interestingly, p53 represses a subset of its activation targets before MDM2 inhibition. GRO-seq uncovered a plethora of gene-specific regulatory features affecting key survival and apoptotic genes within the p53 network. p53 regulates hundreds of enhancer-derived RNAs. Strikingly, direct p53 targets harbor pre-activated enhancers highly transcribed in p53 null cells. Altogether, these results enable the study of many uncharacterized p53 target genes and unexpected regulatory mechanisms. DOI: http://dx.doi.org/10.7554/eLife.02200.001
eLife digest The growth, division and eventual death of the cells in the body are processes that are tightly controlled by hundreds of genes working together. If any of these genes are switched on (or off) in the wrong cell or at the wrong time, it can lead to cancer. It has been known for many years that the protein encoded by one gene in particular—called p53—is nearly always switched off in cancer cells. The p53 protein normally acts like a ‘brake’ to slow the uncontrolled division of cells, and some researchers are working to find ways to switch on this protein in cancer cells. However, this approach appears to only work in specific cases of this disease. For better results, we need to understand how p53 is normally switched on, and what other genes this protein controls once it is activated. Allen et al. have now identified the genes that are directly switched on when cancer cells are treated with a drug that artificially activates the p53 protein. Nearly 200 genes were switched on, and almost three quarters of these genes had not previously been identified as direct targets of p53. Although p53 tends to act as a brake to slow cell division, it is not clear how it distinguishes between its target genes—some of which promote cell survival, while others promote cell death. Allen et al. found that survival genes are switched on more strongly than cell death genes via a range of different mechanisms; this may explain why most cancers can survive drug treatments that reactivate p53. Also, Allen et al. revealed that some p53 target genes are primed to be switched on, even before the p53 protein is activated, by proteins (and other molecules) acting in regions of the DNA outside of the genes. By uncovering many new gene targets for the p53 protein, the findings of Allen et al. could help researchers developing new drugs or treatments for cancer. DOI: http://dx.doi.org/10.7554/eLife.02200.002
Databáze: OpenAIRE
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