eRNAs Are Required for p53-Dependent Enhancer Activity and Gene Transcription
Open accessAbstract
Binding within or nearby target genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulate their transcription and cell-cycle progression. Using genome-wide chromatin-binding profiles, we describe binding of p53 also to regions located distantly from any known p53 target gene. Interestingly, many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions. We demonstrate that these p53-bound enhancer regions (p53BERs) indeed contain enhancer activity and interact intrachromosomally with multiple neighboring genes to convey long-distance p53-dependent transcription regulation. Furthermore, p53BERs produce, in a p53-dependent manner, enhancer RNAs (eRNAs) that are required for efficient transcriptional enhancement of interacting target genes and induction of a p53-dependent cell-cycle arrest. Thus, our results ascribe transcription enhancement activity to p53 with the capacity to regulate multiple genes from a single genomic binding site. Moreover, eRNA production from p53BERs is required for efficient p53 transcription enhancement.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Long-distance transactivation is mediated by the binding of p53 to enhancers.
“long-distance transactivation is reportedly mediated by the binding of p53 to enhancers.30, 65, 66”
From Census and evaluation of p53 target genes (2017) · cites this paper as [65]
Cites
The ENCODE Project Consortium (2007) · Nature · doi:10.1038/nature05874 · Cited by 5,223 · see citing works
Histone H3K27ac separates active from poised enhancers and predicts developmental state
Creyghton, M. P., Cheng, A. W., Welstead, G. G., Kooistra, T., Carey, B. W., Steine, E. J., Hanna, J., Lodato, M. A., Frampton, G. M., Sharp, P. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016071107 · Cited by 4,302 · see citing works
A System for Stable Expression of Short Interfering RNAs in Mammalian Cells
Brummelkamp, T. R., Bernards, R., & Agami, R. (2002) · Science · doi:10.1126/science.1068999 · Cited by 4,295 · see citing works
Self-citationChromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Guttman, M., Amit, I., Garber, M., French, C., Lin, M. F., Feldser, D., Huarte, M., Zuk, O., Carey, B. W., Cassady, J. P., et al. (2009) · Nature · doi:10.1038/nature07672 · Cited by 4,098 · see citing works
Capturing Chromosome Conformation
Dekker, J., Rippe, K., Dekker, M., & Kleckner, N. (2002) · Science · doi:10.1126/science.1067799 · Cited by 3,652 · see citing works
Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., et al. (2007) · Nature Genetics · doi:10.1038/ng1966 · Cited by 3,398 · cited 2× · see citing works
“These include high levels of histone 3 lysine 4monomethylation (H3K4me1), low levels of H3K4 trimethylation (H3K4me3), and high levels of H3K27 acetylation (H3K27Ac) (Heintzman et al., 2007, 2009; Creyghton et al., 2010).”
BackgroundLive or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · see citing works
Histone modifications at human enhancers reflect global cell-type-specific gene expression
Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., et al. (2009) · Nature · doi:10.1038/nature07829 · Cited by 2,533 · see citing works
Widespread transcription at neuronal activity-regulated enhancers
Kim, T.-K., Hemberg, M., Gray, J. M., Costa, A. M., Bear, D. M., Wu, J., Harmin, D. A., Laptewicz, M., Barbara-Haley, K., Kuersten, S., et al. (2010) · Nature · doi:10.1038/nature09033 · Cited by 2,450 · see citing works
A Large Intergenic Noncoding RNA Induced by p53 Mediates Global Gene Repression in the p53 Response
Huarte, M., Guttman, M., Feldser, D., Garber, M., Koziol, M. J., Kenzelmann-Broz, D., Khalil, A. M., Zuk, O., Amit, I., Rabani, M., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.040 · Cited by 2,053 · see citing works
Long Noncoding RNAs with Enhancer-like Function in Human Cells
Ørom, U. A., Derrien, T., Beringer, M., Gumireddy, K., Gardini, A., Bussotti, G., Lai, F., Zytnicki, M., Notredame, C., Huang, Q., et al. (2010) · Cell · doi:10.1016/j.cell.2010.09.001 · Cited by 1,721 · see citing works
A User's Guide to the Encyclopedia of DNA Elements (ENCODE)
The ENCODE Project Consortium (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001046 · Cited by 1,495 · see citing works
A Global Map of p53 Transcription-Factor Binding Sites in the Human Genome
Wei, C.-L., Wu, Q., Vega, V. B., Chiu, K. P., Ng, P., Zhang, T., Shahab, A., Yong, H. C., Fu, Y., Weng, Z., et al. (2006) · Cell · doi:10.1016/j.cell.2005.10.043 · Cited by 1,141 · see citing works
Stable suppression of tumorigenicity by virus-mediated RNA interference
Brummelkamp, T. R., Bernards, R., & Agami, R. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00122-8 · Cited by 1,137 · see citing works
Self-citationA Large Fraction of Extragenic RNA Pol II Transcription Sites Overlap Enhancers
De Santa, F., Barozzi, I., Mietton, F., Ghisletti, S., Polletti, S., Tusi, B. K., Muller, H., Ragoussis, J., Wei, C.-L., & Natoli, G. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000384 · Cited by 934 · see citing works
Enhancer function: new insights into the regulation of tissue-specific gene expression
Ong, C.-T., & Corces, V. G. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2957 · Cited by 929 · see citing works
Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA
Wang, D., García-Bassets, I., Benner, C. W., Li, W., Su, X. B., Zhou, Y., Qiu, J., Liu, W., Kaikkonen, M. U., Ohgi, K. A., et al. (2011) · Nature · doi:10.1038/nature10006 · Cited by 820 · see citing works
Lawrence, J. B., Oxvig, C., Overgaard, M. T., Sottrup-Jensen, L., Gleich, G. J., Hays, L. G., Yates, J. R., & Conover, C. A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3149 · Cited by 706 · see citing works
Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., Broz, D. K., Basak, S., Park, E. J., McLaughlin, M. E., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.035 · Cited by 533 · see citing works
The pathological response to DNA damage does not contribute to p53-mediated tumour suppression
Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B., & Evan, G. I. (2006) · Nature · doi:10.1038/nature05077 · Cited by 382 · see citing works
Splinter, E., de Wit, E., Nora, E. P., Klous, P., van de Werken, H. J. G., Zhu, Y. K., Kaaij, L. J. T., van IJcken, W. F. J., Gribnau, J. H., Heard, É., et al. (2011) · Genes & Development · doi:10.1101/gad.633311 · Cited by 305 · see citing works
Conover, C. A., Bale, L. K., Overgaard, M. T., Johnstone, E. W., Laursen, U. H., Füchtbauer, E., Oxvig, C., & van Deursen, J. (2004) · Development · doi:10.1242/dev.00997 · Cited by 304 · see citing works
A rapid micro chromatin immunoprecipitation assay (ChIP)
Dahl, J. A., & Collas, P. (2008) · Nature Protocols · doi:10.1038/nprot.2008.68 · Cited by 284 · see citing works
A Genetic Screen Identifies PITX1 as a Suppressor of RAS Activity and Tumorigenicity
Kolfschoten, I., van Leeuwen, B., Berns, K., Mullenders, J., Beijersbergen, R. L., Bernards, R., Voorhoeve, P. M., & Agami, R. (2005) · Cell · doi:10.1016/j.cell.2005.04.017 · Cited by 273 · see citing works
Self-citationLi, M., He, Y., Dubois, W., Wu, X., Shi, J., & Huang, J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.01.020 · Cited by 264 · see citing works
BRD7 is a candidate tumour suppressor gene required for p53 function
Drost, J., Mantovani, F., Tocco, F., Elkon, R., Comel, A., Holstege, H. H., Kerkhoven, R. M., Jonkers, J., Voorhoeve, P. M., Agami, R., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2038 · Cited by 199 · see citing works
Self-citationThe tumor-suppressive functions of the human INK4A locus
Voorhoeve, P. M., & Agami, R. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00223-x · Cited by 194 · see citing works
Self-citationEnhancers: emerging roles in cell fate specification
Ong, C., & Corces, V. G. (2012) · The EMBO Reports · doi:10.1038/embor.2012.52 · Cited by 144 · see citing works
The STAT3-IGFBP5 axis is critical for IL-6/gp130-induced premature senescence in human fibroblasts
Kojima, H., Kunimoto, H., Inoue, T., & Nakajima, K. (2012) · Cell Cycle · doi:10.4161/cc.11.4.19172 · Cited by 114 · see citing works
Schultz, D., Vanderveer, L., Buetow, K. H., Boente, M. P., Ozols, R. F., Hamilton, T. C., & Godwin, A. K. (1995) · PubMed · Cited by 92 · see citing works
Characterization of the common fragile site FRA9E and its potential role in ovarian cancer
Callahan, G., Denison, S. R., Phillips, L. A., Shridhar, V., & Smith, D. I. (2003) · Oncogene · doi:10.1038/sj.onc.1206171 · Cited by 69 · see citing works
The complex transcription regulatory landscape of our genome: control in three dimensions
Splinter, E., & de Laat, W. L. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.344 · Cited by 64 · see citing works
Slobodin, B., & Gerst, J. E. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-005-8_24 · Cited by 40 · see citing works
Chander, H., Halpern, M., Resnick‐Silverman, L., Manfredi, J. J., & Germain, D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022456 · Cited by 32 · see citing works
Haim-Vilmovsky, L., Gadir, N., Herbst, R. H., et al. (2011) · RNA · doi:10.1261/rna.029637.111 · Cited by 24 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Gene regulation by long non-coding RNAs and its biological functions
Statello, L., Guo, C.-J., Chen, L.-L., & Huarte, M. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00315-9 · Cited by 4,991 · see citing works
A high-resolution map of the three-dimensional chromatin interactome in human cells
Jin, F., Li, Y., Dixon, J. R., Selvaraj, S., Ye, Z., Lee, A. Y., Yen, C.-A., Schmitt, A. D., Espinoza, C. A., & Ren, B. (2013) · Nature · doi:10.1038/nature12644 · Cited by 1,208 · see citing works
The multiple mechanisms that regulate p53 activity and cell fate
Hafner, A., Bulyk, M. L., Jambhekar, A., & Lahav, G. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0110-x · Cited by 1,129 · see citing works
Long-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102 · see citing works
Census and evaluation of p53 target genes
Fischer, M. (2017) · Oncogene · doi:10.1038/onc.2016.502 · Cited by 971 · see citing works
Kaikkonen, M. U., Spann, N. J., Heinz, S., Romanoski, C. E., Allison, K. A., Stender, J. D., Chun, H. B., Tough, D. F., Prinjha, R. K., Benner, C., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.07.010 · Cited by 672 · see citing works
Topology of mammalian developmental enhancers and their regulatory landscapes
de Laat, W., & Duboule, D. (2013) · Nature · doi:10.1038/nature12753 · Cited by 521 · see citing works
Self-citationDimitrova, N., Zamudio, J. R., Jong, R. M., Soukup, D., Resnick, R., Sarma, K., Ward, A. J., Raj, A., Lee, J. T., Sharp, P. A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.025 · Cited by 445 · see citing works
RNA Binding to CBP Stimulates Histone Acetylation and Transcription
Bose, D. A., Donahue, G., Reinberg, D., Shiekhattar, R., Bonasio, R., & Berger, S. L. (2017) · Cell · doi:10.1016/j.cell.2016.12.020 · Cited by 426 · see citing works
Fischer, M., Grossmann, P., Padi, M., & DeCaprio, J. A. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw523 · Cited by 330 · see citing works
CRISPR/Cas9-based engineering of the epigenome
Pulecio, J., Verma, N., Mejía-Ramírez, E., Huangfu, D., & Raya, A. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.09.006 · Cited by 300 · see citing works
Transcription in Living Cells: Molecular Mechanisms of Bursting
Rodriguez, J., & Larson, D. R. (2020) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-011520-105250 · Cited by 224 · see citing works
Léveillé, N., Melo, C. A., Rooijers, K., Díaz-Lagares, A., Melo, S. A., Korkmaz, G., Lopes, R., Moqadam, F. A., Maia, A. R., Wijchers, P. J., et al. (2015) · Nature Communications · doi:10.1038/ncomms7520 · Cited by 183 · see citing works
Self-citationHistone Deacetylases Positively Regulate Transcription through the Elongation Machinery
Greer, C. B., Tanaka, Y., Kim, Y. J., Xie, P., Zhang, M. Q., Park, I.-H., & Kim, T. H. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.10.013 · Cited by 174 · see citing works
Xie, H., Ma, K., Zhang, K., Zhou, J., Li, L., Yang, W., Gong, Y., Cai, L., & Gong, K. (2021) · Cell Death & Disease · doi:10.1038/s41419-020-03229-8 · Cited by 155 · see citing works
Integrative genomic analysis reveals widespread enhancer regulation by p53 in response to DNA damage
Younger, S. T., Kenzelmann-Broz, D., Jung, H., Attardi, L. D., & Rinn, J. L. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv284 · Cited by 99 · see citing works
Kang, Y., Kim, Y. W., Kang, J., & Kim, A. (2021) · The FASEB Journal · doi:10.1096/fj.202100488r · Cited by 93 · see citing works
A gene expression atlas of early craniofacial development
Brunskill, E. W., Potter, A. S., Distasio, A., Dexheimer, P., Plassard, A., Aronow, B. J., & Potter, S. S. (2014) · Developmental Biology · doi:10.1016/j.ydbio.2014.04.016 · Cited by 81 · see citing works
Expanding the p53 regulatory network: LncRNAs take up the challenge
Grossi, E., Sánchez, Y., & Huarte, M. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2015.07.011 · Cited by 78 · see citing works
Zhan, H., Xie, H., Zhou, Q., Liu, Y., & Huang, W. (2018) · ACS Synthetic Biology · doi:10.1021/acssynbio.8b00202 · Cited by 36 · see citing works
Coleman, D. J., Garcia, G., Hyter, S., Jang, H. S., Chagani, S., Liang, X., Larue, L., Ganguli-Indra, G., & Indra, A. K. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004321 · Cited by 17 · see citing works
- Authors
- Melo, C. A., Drost, J., Wijchers, P. J., van de Werken, H., de Wit, E., Vrielink, J. A. F. O., Elkon, R., Melo, S. A., Léveillé, N., Kalluri, R., de Laat, W., & Agami, R.
- Affiliations
- The Netherlands Cancer Institute (NL)
- University Medical Center Utrecht (NL)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Corresponding author
- Agami, Reuven
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 49
- Issue
- 3
- Pages
- 524-535
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2132257972
- Cited by
- 544
- References
- 35
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 24 · 2023: 31 · 2022: 25 · 2021: 52 · 2020: 39 · 2019: 30 · 2018: 46 · 2017: 43 · 2016: 56 · 2015: 56 · 2014: 54 · 2013: 53
- FWCI
- 20.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- enhancer RNA, p53, enhancers, long-range transcriptional regulation, p53 binding sites, chromatin binding, cell cycle arrest, gene transcription, tumor suppressor
- MeSH terms
- Chromatin, Chromosomes, Human, Enhancer Elements, Genetic, Genes, Humans, Models, Genetic, Protein Binding, RNA, RNA, Messenger, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, RNA, Untranslated, Cell Cycle Checkpoints, MCF-7 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
