Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity

Andrysík, Zdeněk; Galbraith, Matthew D.; Guarnieri, Anna L.; Zaccara, Sara; Sullivan, Kelly D.; Pandey, Ahwan; MacBeth, Morgan; Inga, Alberto; Espinosa, Joaquín M.

doi:10.1101/gr.220533.117

Cited by 139 publications

(220 citation statements)

References 42 publications

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“…Despite this activity, the large majority of p53 genomic binding events occur within regions that are accessible before p53 engagement (10,48,54,59), similar to what is observed for glucocorticoid receptor binding (66). These regions also contain chromatin modifications associated with active CRE, including H3K27ac and H3K4me1/2 before p53 binding (1,48,54,59,60,60). Further, p53 depletion does not alter basal CRE-associated chromatin modifications or chromatin structure at the large majority of CRE (48,54).…”

Section: The Requirement For Other Transcription Factors Co-regulatinmentioning

confidence: 67%

“…We then examined the activity of our putative CREs using the model human colon carcinoma cell line HCT116 which is well-suited for studying p53-dependent transcriptional activity. Our 296 potential p53dependent CREs clustered into two groups based on p53 occupancy using ChIP-seq data from HCT116 cells (1). 169 out of 296 regions were scored as p53 binding sites (peaks) by MACS (Bound, Figure 1B), whereas 127 regions lacked measurable p53 binding (Unbound, Figure 1C).…”

Section: Resultsmentioning

confidence: 99%

“…6A.) These data suggest that other factors are likely responsible for establishing and maintaining chromatin structure and basal activity at the majority of p53-bound CREs. Recent reports suggest that p53 binding and activity is strongly influenced by cell type-specific chromatin accessibility (1,2,54), which itself is controlled by differential transcription factor activity (11,12,(68)(69)(70). How p53 functions across various cell and tissue contexts is still a vital and open question, but recent reports suggested that p53 binding and activity can be influenced by cell type (2,54,71).…”

Section: The Requirement For Other Transcription Factors Co-regulatinmentioning

confidence: 99%

“…The master tumor suppressor p53 is a transcription factor with key roles in preserving genome fidelity and cellular homeostasis. In support of these activities, p53 regulates a core transcriptional program involved in cellular processes like cell cycle arrest, apoptosis, DNA repair, and senescence (1)(2)(3). Loss of p53 activity is strongly linked to increased cancer risk and decreased life expectancy, and misregulation of p53 is associated with numerous other human disorders.…”

Section: Introductionmentioning

confidence: 99%

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Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Catizone

Uzunbas

Celadova

et al. 2019

Preprint

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The master tumor suppressor p53 controls transcription of a wide-ranging gene network involved in apoptosis, cell cycle arrest, DNA damage repair, and senescence. Recent studies revealed pervasive binding of p53 to cis-regulatory elements (CRE), which are non-coding segments of DNA that spatially and temporally control transcription through the combinatorial binding of local transcription factors (TFs). Although the role of p53 as a strong trans-activator of gene expression is well known, the coregulatory factors and local sequences acting at p53-bound CREs are comparatively understudied. We designed and executed a massively parallel reporter assay (MPRA) to investigate the effect of transcription factor binding motifs and local sequence context on p53-bound CRE activity. Our data indicate that p53-bound CREs are both positively and negatively affected by alterations in local sequence context and changes to co-regulatory TF motifs. We identified a SP1/KLF family motif located in an intronic p53 CRE that is required for the endogenous expression of the p53-dependent gene CCNG1. We also identified ATF3 as a factor that co-regulates the expression of the p53-dependent gene GDF15 through binding with p53 in an upstream CRE. Loss of either p53 or ATF3 severely reduces CRE activity and alters endogenous GDF15 mRNA levels in the cell. Our data suggests that p53 has the flexibility to cooperate with a variety of transcription factors in order to regulate CRE activity. By utilizing different sets of co-factors across CREs, we hypothesize that p53 activity is guarded against loss of any one regulatory partner allowing for dynamic and redundant control of p53mediated transcription.Recent evidence suggests that sequence variation within cis-regulatory elements (CREs) can influence p53 binding, transcriptional activity, and tumor suppressor function (5-7) . The critical nature of the core p53 response element (p53RE) on p53 binding and CRE activity is well understood (8-10), but the influence of local sequence variation and the role of transcription factor motifs outside of the p53RE on p53 activity remains an open and vital question.Cis-regulatory elements, such as promoters and enhancers, govern gene expression through temporal, spatial, and quantitative control of transcription (11,12). While multiple models for CRE function have been proposed, the majority involve cooperative binding and activity of multiple transcription factors and cofactors acting locally to fine-tune gene expression (11)(12)(13). The presence and availability of transcription factors, repressors, and other cofactors vary across cell states such as development, stress, disease, and cell type (14-17). This variability provides a mechanism for differential CRE activity and downstream gene expression. Loss of transcription factor binding within a CRE, through variation in DNA sequence or through changes in trans-factor availability, can strongly influence CRE activity and gene expression (11,12,18), with direct implications in numerous developmental and d...

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Section: The Requirement For Other Transcription Factors Co-regulatinmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: The Requirement For Other Transcription Factors Co-regulatinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Catizone

Uzunbas

Celadova

et al. 2019

Preprint

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“…Since transcriptional changes caused by Nutlin treatment are invariably multifunctional (Andrysik et al, 2017), we first asked if differences in cell outcome could be explained by translatome differences. To investigate this possibility, we chose two cell lines which are known to respond differently to treatment with Nutlin as a model system.…”

Section: The Translatomes Of Cells Undergoing Apoptosis or Cell-cyclementioning

confidence: 99%

p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30

Rizzotto

Zaccara

Rossi

et al. 2019

Preprint

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Activation of p53 by the small molecule Nutlin can result in a combination of cell cycle arrest and apoptosis. The relative strength of these events is difficult to predict by classical gene expression analysis, leaving uncertainty as to the therapeutic benefits of Nutlin. Here, we report a new translational control mechanism shaping p53-dependent apoptosis. Using polysome profiling, we establish Nutlin-induced apoptosis to be associated with the enhanced translation of mRNAs carrying multiple copies of a newly identified 3'UTR CG-rich motif mediating p53-dependent death (CGPD-motif). We identified PCBP2 and DHX30 as CGPDmotif interactors. We found that in cells undergoing persistent cell cycle arrest in response to Nutlin, CGPD-motif mRNAs are repressed by the PCBP2-dependent binding of DHX30 to the motif. Thus, upon DHX30 depletion in these cells, the translation of CGPD-motif mRNAs is increased, and the response to Nutlin shifts towards apoptosis. Instead, DHX30 inducible overexpression in SJSA1 cells, that undergo Nutlin-induced apoptosis, leads to decreased translation of CGPD-motif mRNAs. Overall, this work establishes the role of PCBP2-DHX30 in controlling the translation of CGPD-motif mRNAs and thus provide a new mechanism to modulate the induction of p53-dependent apoptosis.

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The landscape of human p53‐regulated long non‐coding RNAs reveals critical host gene co‐regulation

2023

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The role of long non-coding RNAs (lncRNAs) in p53-mediated tumor suppression has become increasingly appreciated in the past decade. Thus, the identification of p53-regulated lncRNAs can be a promising starting point to select and prioritize lncRNAs for functional analyses. By integrating transcriptome and transcription factor-binding data, we identified 379 lncRNAs that are recurrently differentially regulated by p53. Dissecting the mechanisms by which p53 regulates many of them, we identified sets of lncRNAs regulated either directly by p53 or indirectly through the p53-RFX7 and p53-p21-DREAM/RB:E2F pathways. Importantly, we identified multiple p53-responsive lncRNAs that are co-regulated with their protein-coding host genes, revealing an important mechanism by which p53 may regulate lncRNAs. Further analysis of transcriptome data and clinical data from cancer patients showed that recurrently p53-regulated lncRNAs are associated with patient survival. Together, the integrative analysis of the landscape of p53-regulated lncRNAs provides a powerful resource facilitating the identification of lncRNA function and displays the mechanisms of p53-dependent regulation that could be exploited for developing anticancer approaches.

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Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity

Cited by 139 publications

References 42 publications

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

Locally acting transcription factors are required for p53-dependent cis-regulatory element activity

p53-induced apoptosis is specified by a translation program regulated by PCBP2 and DHX30

The landscape of human p53‐regulated long non‐coding RNAs reveals critical host gene co‐regulation

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