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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2014-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/02200 |
| _version_ | 1811180507389493248 |
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| author | Mary Ann Allen Zdenek Andrysik Veronica L Dengler Hestia S Mellert Anna Guarnieri Justin A Freeman Kelly D Sullivan Matthew D Galbraith Xin Luo W Lee Kraus Robin D Dowell Joaquin M Espinosa |
| author_facet | Mary Ann Allen Zdenek Andrysik Veronica L Dengler Hestia S Mellert Anna Guarnieri Justin A Freeman Kelly D Sullivan Matthew D Galbraith Xin Luo W Lee Kraus Robin D Dowell Joaquin M Espinosa |
| author_sort | Mary Ann Allen |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T09:04:27Z |
| format | Article |
| id | doaj.art-ed7fdb31069f44269a183d27ea24807e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:04:27Z |
| publishDate | 2014-05-01 |
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| series | eLife |
| spelling | doaj.art-ed7fdb31069f44269a183d27ea24807e2022-12-22T04:32:41ZengeLife Sciences Publications LtdeLife2050-084X2014-05-01310.7554/eLife.02200Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanismsMary Ann Allen0Zdenek Andrysik1Veronica L Dengler2Hestia S Mellert3Anna Guarnieri4Justin A Freeman5Kelly D Sullivan6Matthew D Galbraith7Xin Luo8W Lee Kraus9Robin D Dowell10Joaquin M Espinosa11Howard Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United States; BioFrontiers Institute, Boulder, United States; Computational Biosciences Program, University of Colorado, Denver–Anschutz Medical Campus, Aurora, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesSignalling and Gene Regulation Laboratory, Cecil H and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, United StatesSignalling and Gene Regulation Laboratory, Cecil H and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United States; BioFrontiers Institute, Boulder, United StatesHoward Hughes Medical Institute, University of Colorado, Boulder, Boulder, United States; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Boulder, United StatesThe 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.https://elifesciences.org/articles/02200tumor supressorgenomicp21PUMAPIG3eRNA |
| spellingShingle | Mary Ann Allen Zdenek Andrysik Veronica L Dengler Hestia S Mellert Anna Guarnieri Justin A Freeman Kelly D Sullivan Matthew D Galbraith Xin Luo W Lee Kraus Robin D Dowell Joaquin M Espinosa Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms eLife tumor supressor genomic p21 PUMA PIG3 eRNA |
| title | 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_short | 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 |
| topic | tumor supressor genomic p21 PUMA PIG3 eRNA |
| url | https://elifesciences.org/articles/02200 |
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