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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53966 | GEO | 2014/05/15

SECONDARY ACCESSION(S): PRJNA234049

REPOSITORIES: GEO

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

Project 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.DOI: http://dx.doi.org/10.7554/eLife.02200.001.

| S-EPMC4033189 | biostudies-literature

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

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-05-15 | E-GEOD-53966 | biostudies-arrayexpress

Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (microarray)

Project description:HCT116 microarray done 12 hours after treatment with DMSO (control) or Nutlin

2014-05-15 | GSE53965 | GEO

Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (microarray)

Project description:HCT116 microarray done 12 hours after treatment with DMSO (control) or Nutlin Total RNA from HCT116 cells was harvested with an RNeasy kit (Qiagen) and analyzed on Affymetrix HuGene 1.0 ST arrays following the manufacturer’s instructions. Microarray data were processed using Partek Genomics Suite 6.6. Anova was used to call differentially expressed genes for which any isoform showed a fold change > |+/-1.5| with FDR <0.05. There were 362 genes called as upregulated and 367 genes as downregulated.

2014-05-15 | E-GEOD-53965 | biostudies-arrayexpress

Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (GRO-Seq)

Project description:GRO-seq of HCT116 cells treated with Nutlin to activate p53

2014-05-15 | GSE53964 | GEO

Global analysis of p53-regulated transcription reveals its direct targets and unexpected regulatory mechanisms (GRO-Seq)

Project description:GRO-seq of HCT116 cells treated with Nutlin to activate p53 HCT116 cells were treated with Nutlin or DMSO for 1 hour

2014-05-15 | E-GEOD-53964 | biostudies-arrayexpress

Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses.

Project description:The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression.

| S-EPMC3656320 | biostudies-literature

Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode.

Project description:Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins, the mechanisms of acetylation-mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 (also known as TP53) was an early example of non-histone protein acetylation and its precise role remains unclear. Lysine acetylation often creates binding sites for bromodomain-containing 'reader' proteins. Here we use a proteomic screen to identify the oncoprotein SET as a major cellular factor whose binding with p53 is dependent on CTD acetylation status. SET profoundly inhibits p53 transcriptional activity in unstressed cells, but SET-mediated repression is abolished by stress-induced acetylation of p53 CTD. Moreover, loss of the interaction with SET activates p53, resulting in tumour regression in mouse xenograft models. Notably, the acidic domain of SET acts as a 'reader' for the unacetylated CTD of p53 and this mechanism of acetylation-dependent regulation is widespread in nature. For example, acetylation of p53 also modulates its interactions with similar acidic domains found in other p53 regulators including VPRBP (also known as DCAF1), DAXX and PELP1 (refs. 7, 8, 9), and computational analysis of the proteome has identified numerous proteins with the potential to serve as acidic domain readers and lysine-rich ligands. Unlike bromodomain readers, which preferentially bind the acetylated forms of their cognate ligands, the acidic domain readers specifically recognize the unacetylated forms of their ligands. Finally, the acetylation-dependent regulation of p53 was further validated in vivo by using a knock-in mouse model expressing an acetylation-mimicking form of p53. These results reveal that acidic-domain-containing factors act as a class of acetylation-dependent regulators by targeting p53 and, potentially, other proteins.

| S-EPMC5333498 | biostudies-literature

Global Analysis of Enhancer Targets Reveals Convergent Enhancer-Driven Regulatory Modules.

Project description:Single-cell screens enable high-throughput functional assessment of enhancers in their endogenous genomic context. However, the design of current studies limits their application to identifying the primary gene targets of enhancers. Here, we improve the experimental and computational parameters of single-cell enhancer screens to identify the secondary gene targets of enhancers. Our analysis of >500 putative enhancers in K562 cells reveals an interwoven enhancer-driven gene regulatory network. We find that enhancers from distinct genomic loci converge to modulate the expression of common sub-modules, including the α- and β-globin loci, by directly regulating transcription factors. Our analysis suggests that several genetic variants associated with myeloid blood cell traits alter the activity of a distal enhancer of MYB (∼140 kb away), with downstream consequences on hemoglobin genes expression and cell state. These data have implications for the understanding of enhancer-associated traits and emphasize the flexibility of controlling transcriptional systems by modifying enhancer activity.

| S-EPMC6904118 | biostudies-literature

Global properties of regulatory sequences are predicted by transcription factor recognition mechanisms.

Project description:BackgroundMammalian genomes contain millions of putative regulatory sequences, which are delineated by binding of multiple transcription factors. The degree to which spacing and orientation constraints among transcription factor binding sites contribute to the recognition and identity of regulatory sequence is an unresolved but important question that impacts our understanding of genome function and evolution. Global mechanisms that underlie phenomena including the size of regulatory sequences, their uniqueness, and their evolutionary turnover remain poorly described.ResultsHere, we ask whether models incorporating different degrees of spacing and orientation constraints among transcription factor binding sites are broadly consistent with several global properties of regulatory sequence. These properties include length, sequence diversity, turnover rate, and dominance of specific TFs in regulatory site identity and cell type specification. Models with and without spacing and orientation constraints are generally consistent with all observed properties of regulatory sequence, and with regulatory sequences being fundamentally small (~ 1 nucleosome). Uniqueness of regulatory regions and their rapid evolutionary turnover are expected under all models examined. An intriguing issue we identify is that the complexity of eukaryotic regulatory sites must scale with the number of active transcription factors, in order to accomplish observed specificity.ConclusionsModels of transcription factor binding with or without spacing and orientation constraints predict that regulatory sequences should be fundamentally short, unique, and turn over rapidly. We posit that the existence of master regulators may be, in part, a consequence of evolutionary pressure to limit the complexity and increase evolvability of regulatory sites.

| S-EPMC8496038 | biostudies-literature

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