Dissecting the DNA binding landscape and gene regulatory network of p63 and p53
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Germany
- Max Planck Institute for Molecular Genetics, Germany
- Queen's University Belfast, United Kingdom
Abstract
The transcription factor p53 is the best-known tumor suppressor, but its sibling p63 is a master regulator of epidermis development and a key oncogenic driver in squamous cell carcinomas (SCC). Despite multiple gene expression studies becoming available, the limited overlap of reported p63-dependent genes has made it difficult to decipher the p63 gene regulatory network. Particularly, analyses of p63 response elements differed substantially among the studies. To address this intricate data situation, we provide an integrated resource that enables assessing the p63-dependent regulation of any human gene of interest. We use a novel iterative de novo motif search approach in conjunction with extensive ChIP-seq data to achieve a precise global distinction between p53 and p63 binding sites, recognition motifs, and potential co-factors. We integrate these data with enhancer:gene associations to predict p63 target genes and identify those that are commonly de-regulated in SCC representing candidates for prognosis and therapeutic interventions.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
-
Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiationNCBI Gene Expression Omnibus, GSE59824.
-
p63 attenuates epithelial to mesenchymal potential in an experimental prostate cell modelNCBI Gene Expression Omnibus, GSE43111.
-
Ras and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional programNCBI Gene Expression Omnibus, GSE60814.
-
SOX2 and p63 colocalize at genetic loci in squamous cell carcinomasNCBI Gene Expression Omnibus, GSE46837.
-
ΔNp63α Suppresses TGFB2 Expression and RHOA Activity to Drive Cell Proliferation in Squamous Cell CarcinomasNCBI Gene Expression Omnibus, GSE111619.
-
p63 regulates an adhesion programme and cell survival in epithelial cellsNCBI Gene Expression Omnibus, GSE20286.
-
ΔNp63α represses anti-proliferative genes via H2A.Z depositionNCBI Gene Expression Omnibus, GSE40462.
-
Control of p53-dependent transcription and enhancer activity by the p53 family member p63NCBI Gene Expression Omnibus, GSE111009.
-
p63 establishes epithelial enhancers at critical craniofacial development genesNCBI Gene Expression Omnibus, GSE126397.
-
TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal AdenocarcinomaNCBI Gene Expression Omnibus, GSE115462.
-
SOX2 and p63 colocalize at genetic loci in squamous cell carcinomasNCBI Gene Expression Omnibus, GSE47058.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (FI 1993/2-1)
- Martin Fischer
Bundesministerium für Bildung und Forschung (031L016D)
- Steve Hoffmann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ashish Lal, National Institutes of Health, United States
Version history
- Received: September 21, 2020
- Accepted: December 1, 2020
- Accepted Manuscript published: December 2, 2020 (version 1)
- Version of Record published: December 14, 2020 (version 2)
Copyright
© 2020, Riege et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,334
- views
-
- 364
- downloads
-
- 22
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Dissecting the DNA binding landscape and gene regulatory network of p63 and p53
eLife 9:e63266.
https://doi.org/10.7554/eLife.63266
Further reading
-
- Chromosomes and Gene Expression
Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription-site-proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.
-
- Chromosomes and Gene Expression
- Genetics and Genomics
Heterogeneity in endothelial cell (EC) sub-phenotypes is becoming increasingly appreciated in atherosclerosis progression. Still, studies quantifying EC heterogeneity across whole transcriptomes and epigenomes in both in vitro and in vivo models are lacking. Multiomic profiling concurrently measuring transcriptomes and accessible chromatin in the same single cells was performed on six distinct primary cultures of human aortic ECs (HAECs) exposed to activating environments characteristic of the atherosclerotic microenvironment in vitro. Meta-analysis of single-cell transcriptomes across 17 human ex vivo arterial specimens was performed and two computational approaches quantitatively evaluated the similarity in molecular profiles between heterogeneous in vitro and ex vivo cell profiles. HAEC cultures were reproducibly populated by four major clusters with distinct pathway enrichment profiles and modest heterogeneous responses: EC1-angiogenic, EC2-proliferative, EC3-activated/mesenchymal-like, and EC4-mesenchymal. Quantitative comparisons between in vitro and ex vivo transcriptomes confirmed EC1 and EC2 as most canonically EC-like, and EC4 as most mesenchymal with minimal effects elicited by siERG and IL1B. Lastly, accessible chromatin regions unique to EC2 and EC4 were most enriched for coronary artery disease (CAD)-associated single-nucleotide polymorphisms from Genome Wide Association Studies (GWAS), suggesting that these cell phenotypes harbor CAD-modulating mechanisms. Primary EC cultures contain markedly heterogeneous cell subtypes defined by their molecular profiles. Surprisingly, the perturbations used here only modestly shifted cells between subpopulations, suggesting relatively stable molecular phenotypes in culture. Identifying consistently heterogeneous EC subpopulations between in vitro and ex vivo models should pave the way for improving in vitro systems while enabling the mechanisms governing heterogeneous cell state decisions.
