1. Chromosomes and Gene Expression
  2. Genetics and Genomics

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

  1. Konstantin Riege
  2. Helene Kretzmer
  3. Arne Sahm
  4. Simon S McDade
  5. Steve Hoffmann
  6. Martin Fischer  Is a corresponding author
  1. Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Germany
  2. Max Planck Institute for Molecular Genetics, Germany
  3. Queen's University Belfast, United Kingdom
https://doi.org/10.7554/eLife.63266
Share this article
Cite this article
  1. Konstantin Riege
  2. Helene Kretzmer
  3. Arne Sahm
  4. Simon S McDade
  5. Steve Hoffmann
  6. Martin Fischer
(2020)
Dissecting the DNA binding landscape and gene regulatory network of p63 and p53
eLife 9:e63266.
https://doi.org/10.7554/eLife.63266
  2. Download BibTeX
  3. Download .RIS

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.

The following previously published data sets were used

Article and author information

Author details

  1. Konstantin Riege

    Computational Biology, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  2. Helene Kretzmer

    Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.

  3. Arne Sahm

    Computational Biology Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7330-1790

  4. Simon S McDade

    Queen's University Belfast, Belfast, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Steve Hoffmann

    Computational Biology Group, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.

  6. Martin Fischer

    Computational Biology, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany
    For correspondence
    Martin.Fischer@leibniz-fli.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3429-1876

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

  1. Ashish Lal, National Institutes of Health, United States

Version history

  1. Received: September 21, 2020
  2. Accepted: December 1, 2020
  3. Accepted Manuscript published: December 2, 2020 (version 1)
  4. 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

  • 2,215
    Page views
  • 354
    Downloads
  • 21
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

  1. Konstantin Riege
  2. Helene Kretzmer
  3. Arne Sahm
  4. Simon S McDade
  5. Steve Hoffmann
  6. Martin Fischer
(2020)
Dissecting the DNA binding landscape and gene regulatory network of p63 and p53
eLife 9:e63266.
https://doi.org/10.7554/eLife.63266

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics

    Chromosome-specific maturation of the epigenome in the Drosophila male germline

    James T Anderson, Steven Henikoff, Kami Ahmad
    Research Article

    Spermatogenesis in the Drosophila male germline proceeds through a unique transcriptional program controlled both by germline-specific transcription factors and by testis-specific versions of core transcriptional machinery. This program includes the activation of genes on the heterochromatic Y chromosome, and reduced transcription from the X chromosome, but how expression from these sex chromosomes is regulated has not been defined. To resolve this, we profiled active chromatin features in the testes from wildtype and meiotic arrest mutants and integrate this with single-cell gene expression data from the Fly Cell Atlas. These data assign the timing of promoter activation for genes with germline-enriched expression throughout spermatogenesis, and general alterations of promoter regulation in germline cells. By profiling both active RNA polymerase II and histone modifications in isolated spermatocytes, we detail widespread patterns associated with regulation of the sex chromosomes. Our results demonstrate that the X chromosome is not enriched for silencing histone modifications, implying that sex chromosome inactivation does not occur in the Drosophila male germline. Instead, a lack of dosage compensation in spermatocytes accounts for the reduced expression from this chromosome. Finally, profiling uncovers dramatic ubiquitinylation of histone H2A and lysine-16 acetylation of histone H4 across the Y chromosome in spermatocytes that may contribute to the activation of this heterochromatic chromosome.

    1. Chromosomes and Gene Expression
    2. Developmental Biology

    Transcription: A hub of activity

    Virginia L Pimmett, Mounia Lagha
    Insight

    Imaging experiments reveal the complex and dynamic nature of the transcriptional hubs associated with Notch signaling.

    1. Chromosomes and Gene Expression
    2. Microbiology and Infectious Disease

    PI(3,4,5)P3 allosteric regulation of repressor activator protein 1 controls antigenic variation in trypanosomes

    Abdoulie O Touray, Rishi Rajesh ... Igor Cestari
    Research Article

    African trypanosomes evade host immune clearance by antigenic variation, causing persistent infections in humans and animals. These parasites express a homogeneous surface coat of variant surface glycoproteins (VSGs). They transcribe one out of hundreds of VSG genes at a time from telomeric expression sites (ESs) and periodically change the VSG expressed by transcriptional switching or recombination. The mechanisms underlying the control of VSG switching and its developmental silencing remain elusive. We report that telomeric ES activation and silencing entail an on/off genetic switch controlled by a nuclear phosphoinositide signaling system. This system includes a nuclear phosphatidylinositol 5-phosphatase (PIP5Pase), its substrate PI(3,4,5)P3, and the repressor-activator protein 1 (RAP1). RAP1 binds to ES sequences flanking VSG genes via its DNA binding domains and represses VSG transcription. In contrast, PI(3,4,5)P3 binds to the N-terminus of RAP1 and controls its DNA binding activity. Transient inactivation of PIP5Pase results in the accumulation of nuclear PI(3,4,5)P3, which binds RAP1 and displaces it from ESs, activating transcription of silent ESs and VSG switching. The system is also required for the developmental silencing of VSG genes. The data provides a mechanism controlling reversible telomere silencing essential for the periodic switching in VSG expression and its developmental regulation.