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.
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
-
- 2,567
- views
-
- 396
- downloads
-
- 35
- 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
Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.
-
- Chromosomes and Gene Expression
- Structural Biology and Molecular Biophysics
Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
