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

Abstract
Data availability
Article and author information
Metrics

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

1. Hansen JL
2. Cohen BA
(2021) A Test of the Pioneer Factor Hypothesis
NCBI Gene Expression Omnibus, GSE182191.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE182191

The following previously published data sets were used

1. Partridge EC
2. Chhetri SB
3. Prokop JW
4. Ramaker RC
5. Jansen CS
6. Goh ST
7. Mackiewicz M
8. Newberry KM
9. Brandsmeier LA
10. Meadows SK
11. Messer CL
12. Hardigan AA
13. Coppola CJ
14. Dean EC
15. Jiang S
16. Savic D
17. Mortazavi A
18. Wold BJ
19. Myers RM
20. Mendenhall EM
(2020) Occupancy maps of 208 chromatin-associated proteins in one human cell type
NCBI Gene Expression Omnibus, GSE104247.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104247

Article and author information

Author details

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.

"This ORCID iD identifies the author of this article:" 0000-0001-5343-9066
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.
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.

"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

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.