Pioneer factors as master regulators of the epigenome and cell fate
Abstract
Pioneer factors are transcription factors with the unique ability to initiate opening of closed chromatin. The stability of cell identity relies on robust mechanisms that maintain the epigenome and chromatin accessibility to transcription factors. Pioneer factors counter these mechanisms to implement new cell fates through binding of DNA target sites in closed chromatin and introduction of active-chromatin histone modifications, primarily at enhancers. As master regulators of enhancer activation, pioneers are thus crucial for the implementation of correct cell fate decisions in development, and as such, they hold tremendous potential for therapy through cellular reprogramming. The power of pioneer factors to reshape the epigenome also presents an Achilles heel, as their misexpression has major pathological consequences, such as in cancer. In this Review, we discuss the emerging mechanisms of pioneer factor functions and their roles in cell fate specification, cellular reprogramming and cancer.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The pioneering model of reprogramming has been proposed for OSKM based on their ability to bind to chromatin not normally accessible by transcription factors.
“The pioneering model of reprogramming has been proposed for OSKM based on their ability to bind to chromatin not normally accessible by transcription factors60–62.”
From The NuRD complex cooperates with SALL4 to orchestrate reprogramming (2023) · cites this paper as [62]
Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
METABRIC Group, Curtis, C., Shah, S. P., Chin, S.-F., Turashvili, G., Rueda, O. M., Dunning, M. J., Speed, D., Lynch, A. G., Samarajiwa, S., et al. (2012) · Nature · doi:10.1038/nature10983 · Cited by 6,097 · see citing works
Heintzman, N. D., Stuart, R. K., Hon, G., Fu, Y., Ching, C. W., Hawkins, R. D., Barrera, L. O., Van Calcar, S., Qu, C., Ching, K. A., et al. (2007) · Nature Genetics · doi:10.1038/ng1966 · Cited by 3,398 · see citing works
Direct conversion of fibroblasts to functional neurons by defined factors
Vierbuchen, T., Ostermeier, A., Pang, Z. P., Kokubu, Y., Südhof, T. C., & Wernig, M. (2010) · Nature · doi:10.1038/nature08797 · Cited by 3,017 · see citing works
The mutational landscape of lethal castration-resistant prostate cancer
Grasso, C. S., Wu, Y.-M., Robinson, D. R., Cao, X., Dhanasekaran, S. M., Khan, A. P., Quist, M. J., Jing, X., Lonigro, R. J., Brenner, J. C., et al. (2012) · Nature · doi:10.1038/nature11125 · Cited by 2,517 · see citing works
Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors
Sekiya, S., & Suzuki, A. (2011) · Nature · doi:10.1038/nature10263 · Cited by 846 · see citing works
Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
Soufi, A., Garcia, M. F., Jaroszewicz, A., Osman, N., Pellegrini, M., & Zaret, K. S. (2015) · Cell · doi:10.1016/j.cell.2015.03.017 · Cited by 780 · see citing works
Cooperative Binding of Transcription Factors Orchestrates Reprogramming
Chronis, C., Fiziev, P., Papp, B., Butz, S., Bonora, G., Sabri, S., Ernst, J., & Plath, K. (2017) · Cell · doi:10.1016/j.cell.2016.12.016 · Cited by 555 · see citing works
PU.1 and C/EBPα/β convert fibroblasts into macrophage-like cells
Feng, R., Desbordes, S. C., Xie, H., Tillo, E. S., Pixley, F., Stanley, E. R., & Graf, T. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711961105 · Cited by 348 · see citing works
Voss, T. C., Schiltz, R. L., Sung, M.-H., Yen, P. M., Stamatoyannopoulos, J. A., Biddie, S. C., Johnson, T. A., Miranda, T. B., John, S., & Hager, G. L. (2011) · Cell · doi:10.1016/j.cell.2011.07.006 · Cited by 307 · see citing works
Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells
Johnson, J. L., Georgakilas, G., Petrovic, J., Kurachi, M., Cai, S., Harly, C., Pear, W. S., Bhandoola, A., Wherry, E. J., & Vahedi, G. (2018) · Immunity · doi:10.1016/j.immuni.2018.01.012 · Cited by 226 · see citing works
Induction of a hemogenic program in mouse fibroblasts
Pereira, C.-F., Chang, B., Qiu, J., Niu, X., Papatsenko, D., Hendry, C. E., Clark, N. R., Nomura-Kitabayashi, A., Kovacic, J. C., Ma’ayan, A., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.05.024 · Cited by 216 · see citing works
Jacobs, J., Atkins, M., Davie, K., Imrichova, H., Romanelli, L., Christiaens, V., Hulselmans, G., Potier, D., Wouters, J., Taskiran, I. I., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0140-x · Cited by 155 · see citing works
Takaku, M., Grimm, S. A., Shimbo, T., Perera, L., Menafra, R., Stunnenberg, H. G., Archer, T. K., Machida, S., Kurumizaka, H., & Wade, P. A. (2016) · Genome Biology · doi:10.1186/s13059-016-0897-0 · Cited by 151 · see citing works
Minderjahn, J., Schmidt, A., Fuchs, A., Schill, R., Raithel, J., Babina, M., Schmidl, C., Gebhard, C., Schmidhofer, S., Mendes, K., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-13960-2 · Cited by 136 · see citing works
Ungerbäck, J., Hosokawa, H., Wang, X., Strid, T., Williams, B. A., Sigvardsson, M., & Rothenberg, E. V. (2018) · Genome Research · doi:10.1101/gr.231423.117 · Cited by 77 · see citing works
Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons
Luo, C., Lee, Q. Y., Wapinski, O., Castanon, R., Nery, J. R., Mall, M., Kareta, M. S., Cullen, S. M., Goodell, M. A., Chang, H. Y., et al. (2019) · eLife · doi:10.7554/elife.40197 · Cited by 76 · see citing works
Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes
Lee, Q. Y., Mall, M., Chanda, S., Zhou, B., Sharma, K. S., Schaukowitch, K., Adrian-Segarra, J. M., Grieder, S. D., Kareta, M. S., Wapinski, O. L., et al. (2020) · Nature Cell Biology · doi:10.1038/s41556-020-0490-3 · Cited by 50 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hold out the genome: a roadmap to solving the cis-regulatory code
de Boer, C. G., & Taipale, J. (2024) · Nature · doi:10.1038/s41586-023-06661-w · Cited by 107 · see citing works
The NuRD complex cooperates with SALL4 to orchestrate reprogramming
Wang, B., Li, C., Ming, J., Wu, L., Fang, S., Huang, Y., Lin, L., Liu, H., Kuang, J., Zhao, C., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38543-0 · Cited by 39 · see citing works
“The pioneering model of reprogramming has been proposed for OSKM based on their ability to bindtochromatinnotnormallyaccessiblebytranscriptionfactors 60 – 62 .”
Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Katsuda, T., Sussman, J. H., Ito, K., Katznelson, A., Yuan, S., Takenaka, N., Li, J., Merrell, A. J., Cure, H., Li, Q., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45939-z · Cited by 33 · see citing works
Lim, B., Kamal, A., Gomez Ramos, B., Adrian Segarra, J. M., Ibarra, I. L., Dignas, L., Kindinger, T., Volz, K., Rahbari, M., Rahbari, N., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02081-w · Cited by 17 · see citing works
Zhao, W., Yuan, W., Dong, T., Qi, W., Feng, Z., Li, C., & Sun, Y. (2025) · Communications Biology · doi:10.1038/s42003-025-08160-2 · Cited by 16 · see citing works
Epigenetic preparation of future gene induction kinetics
Xiong, J., & Zhu, B. (2025) · Annual Review of Genetics · doi:10.1146/annurev-genet-012825-093148 · Cited by 12 · see citing works
- Authors
- Balsalobre, A., & Drouin, J.
- Affiliations
- Montreal Clinical Research Institute (CA)
- Corresponding author
- Drouin, Jacques
- ORCID
- Drouin, Jacques
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2022-03-09
- Volume
- 23
- Issue
- 7
- Pages
- 449-464
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- OpenAlex
- W4220833476
- Cited by
- 251
- References
- 18
- Citations by year
- 2026: 36 · 2025: 73 · 2024: 64 · 2023: 59 · 2022: 19
- FWCI
- 5.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (154297_1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- pioneer transcription factors, chromatin accessibility, enhancer activation, histone modifications, cell fate specification, cellular reprogramming, cancer, developmental gene regulation
- MeSH terms
- Epigenome, Cell Differentiation, Chromatin, Humans, Neoplasms, Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
