1. Chromosomes and Gene Expression
  2. Genetics and Genomics

The pioneer factor hypothesis is not necessary to explain ectopic liver gene activation

  1. Jeffrey L Hansen
  2. Kaiser J Loell
  3. Barak A Cohen  Is a corresponding author
  1. Washington University in St. Louis, United States
https://doi.org/10.7554/eLife.73358
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  1. Jeffrey L Hansen
  2. Kaiser J Loell
  3. Barak A Cohen
(2022)
The pioneer factor hypothesis is not necessary to explain ectopic liver gene activation
eLife 11:e73358.
https://doi.org/10.7554/eLife.73358
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Abstract

The Pioneer Factor Hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (nonPFs) that activate batteries of silent genes. The PFH predicts that ectopic gene activation requires the sequential activity of qualitatively different TFs. We tested the PFH by expressing the endodermal PF FOXA1 and nonPF HNF4A in K562 lymphoblast cells. While co-expression of FOXA1 and HNF4A activated a burst of endoderm-specific gene expression, we found no evidence for a functional distinction between these two TFs. When expressed independently, both TFs bound and opened inaccessible sites, activated endodermal genes, and 'pioneered' for each other, although FOXA1 required fewer copies of its motif for binding. A subset of targets required both TFs, but the predominant mode of action at these targets did not conform to the sequential activity predicted by the PFH. From these results we hypothesize an alternative to the PFH where 'pioneer activity' depends not on categorically different TFs but rather on the affinity of interaction between TF and DNA.

Data availability

All genomic sequencing data have been deposited on Gene Expression Omnibus (GEO) under accession number GSE182191.

The following data sets were generated
The following previously published data sets were used

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Author details

  1. Jeffrey L Hansen

    Edison Center for Genome Sciences and Systems Biology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5343-9066

  2. Kaiser J Loell

    Edison Center for Genome Sciences and Systems Biology, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Barak A Cohen

    Edison Center for Genome Sciences and Systems Biology, Washington University in St. Louis, Saint Louis, United States
    For correspondence
    cohen@genetics.wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3350-2715

Funding

National Institute of General Medical Sciences (R01GM092910)

  • Barak A Cohen

National Human Genome Research Institute (T32HG000045)

  • Barak A Cohen

National Institute of General Medical Sciences (T32GM007200)

  • Jeffrey L Hansen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Hansen 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.

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  1. Jeffrey L Hansen
  2. Kaiser J Loell
  3. Barak A Cohen
(2022)
The pioneer factor hypothesis is not necessary to explain ectopic liver gene activation
eLife 11:e73358.
https://doi.org/10.7554/eLife.73358

Share this article

https://doi.org/10.7554/eLife.73358

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