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

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 establ...

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Main Authors:	Allen, Mary Ann, Andrysik, Zdenek, Dengler, Veronica L, Mellert, Hestia S, Guarnieri, Anna, Freeman, Justin A, Sullivan, Kelly D, Galbraith, Matthew D, Luo, Xin, Kraus, W Lee, Dowell, Robin D, Espinosa, Joaquin M
Format:	Online
Language:	English
Published:	eLife Sciences Publications, Ltd 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033189/

id	pubmed-4033189
recordtype	oai_dc
spelling	pubmed-40331892014-06-02 Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms Allen, Mary Ann Andrysik, Zdenek Dengler, Veronica L Mellert, Hestia S Guarnieri, Anna Freeman, Justin A Sullivan, Kelly D Galbraith, Matthew D Luo, Xin Kraus, W Lee Dowell, Robin D Espinosa, Joaquin M Genes and Chromosomes 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. eLife Sciences Publications, Ltd 2014-05-27 /pmc/articles/PMC4033189/ /pubmed/24867637 http://dx.doi.org/10.7554/eLife.02200 Text en Copyright © 2014, Allen et al http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Allen, Mary Ann Andrysik, Zdenek Dengler, Veronica L Mellert, Hestia S Guarnieri, Anna Freeman, Justin A Sullivan, Kelly D Galbraith, Matthew D Luo, Xin Kraus, W Lee Dowell, Robin D Espinosa, Joaquin M
spellingShingle	Allen, Mary Ann Andrysik, Zdenek Dengler, Veronica L Mellert, Hestia S Guarnieri, Anna Freeman, Justin A Sullivan, Kelly D Galbraith, Matthew D Luo, Xin Kraus, W Lee Dowell, Robin D Espinosa, Joaquin M Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms
author_facet	Allen, Mary Ann Andrysik, Zdenek Dengler, Veronica L Mellert, Hestia S Guarnieri, Anna Freeman, Justin A Sullivan, Kelly D Galbraith, Matthew D Luo, Xin Kraus, W Lee Dowell, Robin D Espinosa, Joaquin M
author_sort	Allen, Mary Ann
title	Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms
title_short	Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms
title_full	Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms
title_fullStr	Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms
title_full_unstemmed	Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms
title_sort	global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms
description	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.
publisher	eLife Sciences Publications, Ltd
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033189/
_version_	1612093104866721792

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

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