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.
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References
Iwafuchi-Doi, M. & Zaret, K. S. Cell fate control by pioneer transcription factors. Development 143, 1833–1837 (2016).
Mayran, A. & Drouin, J. Pioneer transcription factors shape the epigenetic landscape. J. Biol. Chem. 293, 13795–13804 (2018).
Larson, E. D., Marsh, A. J. & Harrison, M. M. Pioneering the developmental frontier. Mol. Cell 81, 1640–1650 (2021).
Stewart-Morgan, K. R., Petryk, N. & Groth, A. Chromatin replication and epigenetic cell memory. Nat. Cell Biol. 22, 361–371 (2020).
Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).
Donaghey, J. et al. Genetic determinants and epigenetic effects of pioneer-factor occupancy. Nat. Genet. 50, 250–258 (2018).
Mayran, A. et al. Pioneer factor Pax7 deploys a stable enhancer repertoire for specification of cell fate. Nat. Genet. 50, 259–269 (2018).
Barozzi, I. et al. Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Mol. Cell 54, 844–857 (2014).
Boller, S. et al. Pioneering activity of the C-terminal domain of EBF1 shapes the chromatin landscape for B cell programming. Immunity 44, 527–541 (2016).
Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
van Oevelen, C. et al. C/EBPalpha activates pre-existing and de novo macrophage enhancers during induced pre-B cell transdifferentiation and myelopoiesis. Stem Cell Rep. 5, 232–247 (2015).
Iwafuchi-Doi, M. et al. The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation. Mol. Cell 62, 79–91 (2016).
Cirillo, L. A. & Zaret, K. S. An early developmental transcription factor complex that is more stable on nucleosome core particles than on free DNA. Mol. Cell 4, 961–969 (1999).
Heintzman, N. D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).
Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–837 (2013).
Aydin, B. & Mazzoni, E. O. Cell reprogramming: the many roads to success. Annu. Rev. Cell Dev. Biol. 35, 433–452 (2019).
Horisawa, K. & Suzuki, A. Direct cell-fate conversion of somatic cells: toward regenerative medicine and industries. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 96, 131–158 (2020).
Adams, E. J. et al. FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 571, 408–412 (2019).
Hankey, W., Chen, Z. & Wang, Q. Shaping chromatin states in prostate cancer by pioneer transcription factors. Cancer Res. 80, 2427–2436 (2020).
Sun, Y. et al. HOXA9 reprograms the enhancer landscape to promote leukemogenesis. Cancer Cell 34, 643–658.e5 (2018).
Cao, L. et al. Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer. Cancer Res. 70, 6497–6508 (2010).
Gualdi, R. et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 10, 1670–1682 (1996).
Zaret, K. S. & Mango, S. E. Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr. Opin. Genet. Dev. 37, 76–81 (2016).
McDaniel, S. L. et al. Continued activity of the pioneer factor Zelda is required to drive zygotic genome activation. Mol. Cell 74, 185–195.e4 (2019).
Zhu, F. et al. The interaction landscape between transcription factors and the nucleosome. Nature 562, 76–81 (2018).
Dodonova, S. O., Zhu, F., Dienemann, C., Taipale, J. & Cramer, P. Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function. Nature 580, 669–672 (2020).
Michael, A. K. et al. Mechanisms of OCT4-SOX2 motif readout on nucleosomes. Science 368, 1460–1465 (2020).
Tanaka, H. et al. Interaction of the pioneer transcription factor GATA3 with nucleosomes. Nat. Commun. 11, 4136 (2020).
Fernandez Garcia, M. et al. Structural features of transcription factors associating with nucleosome binding. Mol. Cell 75, 921–932.e6 (2019).
Soufi, A. et al. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 161, 555–568 (2015).
Mayran, A. et al. Pioneer and nonpioneer factor cooperation drives lineage specific chromatin opening. Nat. Commun. 10, 3807 (2019).
Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell 151, 994–1004 (2012).
Nicetto, D. et al. H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification. Science 363, 294–297 (2019).
Koche, R. P. et al. Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 8, 96–105 (2011).
Becker, J. S. et al. Genomic and proteomic resolution of heterochromatin and its restriction of alternate fate genes. Mol. Cell 68, 1023–1037.e15 (2017).
Hildebrand, E. M. & Dekker, J. Mechanisms and functions of chromosome compartmentalization. Trends Biochem. Sci. 45, 385–396 (2020).
Poleshko, A. et al. Genome-nuclear lamina interactions regulate cardiac stem cell lineage restriction. Cell 171, 573–587.e14 (2017).
Stadhouders, R. et al. Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nat. Genet. 50, 238–249 (2018).
Bolt, C. C. et al. Context-dependent enhancer function revealed by targeted inter-TAD relocation. Preprint at bioRxiv https://doi.org/10.1101/2022.01.19.476888 (2022).
Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).
Giresi, P. G. & Lieb, J. D. Isolation of active regulatory elements from eukaryotic chromatin using FAIRE (formaldehyde assisted isolation of regulatory elements). Methods 48, 233–239 (2009).
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y. & Greenleaf, W. J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013).
Li, R. et al. Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming. Genes Dev. 32, 96–111 (2018).
Wapinski, O. L. et al. Rapid chromatin switch in the direct reprogramming of fibroblasts to neurons. Cell Rep. 20, 3236–3247 (2017).
Jozwik, K. M., Chernukhin, I., Serandour, A. A., Nagarajan, S. & Carroll, J. S. FOXA1 directs H3K4 monomethylation at enhancers via recruitment of the methyltransferase MLL3. Cell Rep. 17, 2715–2723 (2016).
King, H. A., Trotter, K. W. & Archer, T. K. Chromatin remodeling during glucocorticoid receptor regulated transactivation. Biochim. Biophys. Acta 1819, 716–726 (2012).
King, H. W. & Klose, R. J. The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells. eLife 6, e22631 (2017).
Takaku, M. et al. GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler. Genome Biol. 17, 36 (2016).
Gao, R. et al. Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate. Cell Res. 29, 486–501 (2019).
Hoffman, J. A., Trotter, K. W., Ward, J. M. & Archer, T. K. BRG1 governs glucocorticoid receptor interactions with chromatin and pioneer factors across the genome. eLife 7, e35073 (2018).
Dyson, H. J. & Wright, P. E. Role of intrinsic protein disorder in the function and interactions of the transcriptional coactivators CREB-binding protein (CBP) and p300. J. Biol. Chem. 291, 6714–6722 (2016).
Alver, B. H. et al. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat. Commun. 8, 14648 (2017).
Jindal, G. A. & Farley, E. K. Enhancer grammar in development, evolution, and disease: dependencies and interplay. Dev. Cell 56, 575–587 (2021).
Huang, P. et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386–389 (2011).
Sekiya, S. & Suzuki, A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475, 390–393 (2011).
Lee, K. et al. FOXA2 is required for enhancer priming during pancreatic differentiation. Cell Rep. 28, 382–393.e7 (2019).
Laganiere, J. et al. Location analysis of estrogen receptor α target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc. Natl Acad. Sci. USA 102, 11651–11656 (2005).
Carroll, J. S. et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122, 33–43 (2005).
Lupien, M. et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958–970 (2008).
Wang, Q. et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138, 245–256 (2009).
Voss, T. C. et al. Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146, 544–554 (2011).
Sherwood, R. I. et al. Discovery of directional and nondirectional pioneer transcription factors by modeling DNase profile magnitude and shape. Nat. Biotechnol. 32, 171–178 (2014).
Swinstead, E. E. et al. Steroid receptors reprogram FoxA1 occupancy through dynamic chromatin transitions. Cell 165, 593–605 (2016).
Glont, S. E., Chernukhin, I. & Carroll, J. S. Comprehensive genomic analysis reveals that the pioneering function of FOXA1 is independent of hormonal signaling. Cell Rep. 26, 2558–2565.e3 (2019).
Paakinaho, V., Swinstead, E. E., Presman, D. M., Grøntved, L. & Hager, G. L. Meta-analysis of chromatin programming by steroid receptors. Cell Rep. 28, 3523–3534.e2 (2019).
Nevil, M., Gibson, T. J., Bartolutti, C., Iyengar, A. & Harrison, M. M. Establishment of chromatin accessibility by the conserved transcription factor Grainy head is developmentally regulated. Development 147, dev185009 (2020).
Jacobs, J. et al. The transcription factor Grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes. Nat. Genet. 50, 1011–1020 (2018).
Cernilogar, F. M. et al. Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2. Nucleic Acids Res. 47, 9069–9086 (2019).
Ungerbäck, J. et al. Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1). Genome Res. 28, 1508–1519 (2018).
Escobar, T. M. et al. Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication. Cell 179, 953–963.e11 (2019).
Busslinger, M., Hurst, J. & Flavell, R. A. DNA methylation and the regulation of globin gene expression. Cell 34, 197–206 (1983).
Bird, A. P. CpG-rich islands and the function of DNA methylation. Nature 321, 209–213 (1986).
Neiman, D. et al. Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers. Proc. Natl Acad. Sci. USA 114, 13525–13530 (2017).
Orlanski, S. et al. Tissue-specific DNA demethylation is required for proper B-cell differentiation and function. Proc. Natl Acad. Sci. USA 113, 5018–5023 (2016).
Jadhav, U. et al. Extensive recovery of embryonic enhancer and gene memory stored in hypomethylated enhancer DNA. Mol. Cell 74, 542–554.e5 (2019).
Reizel, Y. et al. FoxA-dependent demethylation of DNA initiates epigenetic memory of cellular identity. Dev. Cell 56, 602–612.e4 (2021).
Sardina, J. L. et al. Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell 23, 727–741.e9 (2018).
Hahn, M. A. et al. Reprogramming of DNA methylation at NEUROD2-bound sequences during cortical neuron differentiation. Sci. Adv. 5, eaax0080 (2019).
Lio, C. J. et al. TET methylcytosine oxidases: new insights from a decade of research. J. Biosci. 45, 21 (2020).
Yang, Y. A. et al. FOXA1 potentiates lineage-specific enhancer activation through modulating TET1 expression and function. Nucleic Acids Res. 44, 8153–8164 (2016).
Zhang, Y. et al. Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nat. Genet. 48, 1003–1013 (2016).
Vanzan, L. et al. High throughput screening identifies SOX2 as a super pioneer factor that inhibits DNA methylation maintenance at its binding sites. Nat. Commun. 12, 3337 (2021).
von Meyenn, F. et al. Comparative principles of DNA methylation reprogramming during human and mouse in vitro primordial germ cell specification. Dev. Cell 39, 104–115 (2016).
Bronner, C., Alhosin, M., Hamiche, A. & Mousli, M. Coordinated dialogue between UHRF1 and DNMT1 to ensure faithful inheritance of methylated DNA patterns. Genes 10, 65 (2019).
Dufourt, J. et al. Temporal control of gene expression by the pioneer factor Zelda through transient interactions in hubs. Nat. Commun. 9, 5194 (2018).
Tu, W. J. et al. Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells. Sci. Rep. 7, 44825 (2017).
Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).
Pacis, A. et al. Gene activation precedes DNA demethylation in response to infection in human dendritic cells. Proc. Natl Acad. Sci. USA 116, 6938–6943 (2019).
Luo, C. et al. Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons. eLife 8, e40197 (2019).
D’Urso, A. et al. Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory. eLife 5, e16691 (2016).
Horisawa, K. et al. The dynamics of transcriptional activation by hepatic reprogramming factors. Mol. Cell 79, 660–676.e8 (2020).
Pelletier, A., Mayran, A., Omichinski, J. & Drouin, J. Pax7 pioneer action requires both paired and homeo DNA binding domains. Nucleic Acids Res. 49, 7424–7436 (2021).
Hsu, H. T. et al. Recruitment of RNA polymerase II by the pioneer transcription factor PHA-4. Science 348, 1372–1376 (2015).
Lee, C. S., Friedman, J. R., Fulmer, J. T. & Kaestner, K. H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005).
Choi, S. H. et al. DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic Acids Res. 44, 5161–5173 (2016).
Gaskill, M. M., Gibson, T. J., Larson, E. D. & Harrison, M. M. GAF is essential for zygotic genome activation and chromatin accessibility in the early Drosophila embryo. eLife 10, e66668 (2021).
Koromila, T. et al. Odd-paired is a pioneer-like factor that coordinates with Zelda to control gene expression in embryos. eLife 9, e59610 (2020).
Soluri, I. V., Zumerling, L. M., Payan Parra, O. A., Clark, E. G. & Blythe, S. A. Zygotic pioneer factor activity of Odd-paired/Zic is necessary for late function of the Drosophila segmentation network. eLife 9, e53916 (2020).
Hendrickson, P. G. et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat. Genet. 49, 925–934 (2017).
Resnick, R. et al. DUX4-induced histone variants H3.X and H3.Y Mark DUX4 target genes for expression. Cell Rep. 29, 1812–1820.e5 (2019).
Gentsch, G. E., Spruce, T., Owens, N. D. L. & Smith, J. C. Maternal pluripotency factors initiate extensive chromatin remodelling to predefine first response to inductive signals. Nat. Commun. 10, 4269 (2019).
Pálfy, M., Schulze, G., Valen, E. & Vastenhouw, N. L. Chromatin accessibility established by Pou5f3, Sox19b and Nanog primes genes for activity during zebrafish genome activation. PLoS Genet. 16, e1008546 (2020).
Veil, M., Yampolsky, L. Y., Grüning, B. & Onichtchouk, D. Pou5f3, SoxB1, and Nanog remodel chromatin on high nucleosome affinity regions at zygotic genome activation. Genome Res. 29, 383–395 (2019).
Cirillo, L. A. et al. Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J. 17, 244–254 (1998).
Serandour, A. A. et al. Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers. Genome Res. 21, 555–565 (2011).
Charney, R. M. et al. Foxh1 occupies cis-regulatory modules prior to dynamic transcription factor interactions controlling the mesendoderm gene program. Dev. Cell 40, 595–607.e4 (2017).
Holtzinger, A. & Evans, T. Gata4 regulates the formation of multiple organs. Development 132, 4005–4014 (2005).
Zhao, R. et al. GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol. Cell Biol. 25, 2622–2631 (2005).
Watt, A. J., Zhao, R., Li, J. & Duncan, S. A. Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev. Biol. 7, 37 (2007).
Feng, R. et al. PU.1 and C/EBPalpha/beta convert fibroblasts into macrophage-like cells. Proc. Natl Acad. Sci. USA 105, 6057–6062 (2008).
Lin, H. & Grosschedl, R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–267 (1995).
Lin, Y. C. et al. A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat. Immunol. 11, 635–643 (2010).
Johanson, T. M. et al. Transcription-factor-mediated supervision of global genome architecture maintains B cell identity. Nat. Immunol. 19, 1257–1264 (2018).
Mansson, R. et al. Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate. Proc. Natl Acad. Sci. USA 109, 21028–21033 (2012).
Johnson, J. L. et al. Lineage-determining transcription factor TCF-1 initiates the epigenetic identity of T cells. Immunity 48, 243–257.e10 (2018).
Germar, K. et al. T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling. Proc. Natl Acad. Sci. USA 108, 20060–20065 (2011).
Weber, B. N. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63–68 (2011).
Budry, L. et al. The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling. Genes Dev. 26, 2299–2310 (2012).
Lamolet, B. et al. A pituitary cell-restricted T-box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell 104, 849–859 (2001).
Pulichino, A. M. et al. Tpit determines alternate fates during pituitary cell differentiation. Genes Dev. 17, 738–747 (2003).
Pulichino, A. M. et al. Human and mouse Tpit gene mutations cause early onset pituitary ACTH deficiency. Genes Dev. 17, 711–716 (2003).
Luna-Zurita, L. et al. Complex interdependence regulates heterotypic transcription factor distribution and coordinates cardiogenesis. Cell 164, 999–1014 (2016).
He, A. et al. Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease. Nat. Commun. 5, 4907 (2014).
Jia, G. et al. Single cell RNA-seq and ATAC-seq analysis of cardiac progenitor cell transition states and lineage settlement. Nat. Commun. 9, 4877 (2018).
Gurdon, J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).
Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Chronis, C. et al. Cooperative binding of transcription factors orchestrates reprogramming. Cell 168, 442–459.e20 (2017).
Wapinski, O. L. et al. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155, 621–635 (2013).
Park, N. I. et al. ASCL1 reorganizes chromatin to direct neuronal fate and suppress tumorigenicity of glioblastoma stem cells. Cell Stem Cell 21, 209–224.e7 (2017).
Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).
Pataskar, A. et al. NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program. EMBO J. 35, 24–45 (2016).
Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).
Tapscott, S. J. et al. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science 242, 405–411 (1988).
Lee, Q. Y. et al. Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes. Nat. Cell Biol. 22, 401–411 (2020).
Milan, M. et al. FOXA2 controls the cis-regulatory networks of pancreatic cancer cells in a differentiation grade-specific manner. EMBO J. 38, e102161 (2019).
Zhou, Q. & Melton, D. A. Pancreas regeneration. Nature 557, 351–358 (2018).
Hurtado, A., Holmes, K. A., Ross-Innes, C. S., Schmidt, D. & Carroll, J. S. FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat. Genet. 43, 27–33 (2011).
Carroll, J. S. et al. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38, 1289–1297 (2006).
Pomerantz, M. M. et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat. Genet. 47, 1346–1351 (2015).
Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).
Sahu, B. et al. Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J. 30, 3962–3976 (2011).
Zhou, S. et al. Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer. Nat. Commun. 11, 441 (2020).
Thorat, M. A. et al. Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis. J. Clin. Pathol. 61, 327–332 (2008).
Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).
Green, M. R. et al. Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin’s lymphoma. Genes Chromosom. Cancer 50, 313–326 (2011).
Yu, J. et al. Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. Clin. Cancer Res. 17, 1924–1934 (2011).
Hatta, M. & Cirillo, L. A. Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 282, 35583–35593 (2007).
So, C. W. & Cleary, M. L. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood 101, 633–639 (2003).
Young, J. M. et al. DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet. 9, e1003947 (2013).
Lim, K. R. Q., Nguyen, Q. & Yokota, T. DUX4 signalling in the pathogenesis of facioscapulohumeral muscular dystrophy. Int. J. Mol. Sci. 21, 729 (2020).
Bosnakovski, D. et al. The DUX4 homeodomains mediate inhibition of myogenesis and are functionally exchangeable with the Pax7 homeodomain. J. Cell Sci. 130, 3685–3697 (2017).
Minderjahn, J. et al. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1. Nat. Commun. 11, 402 (2020).
Raposo, A. et al. Ascl1 coordinately regulates gene expression and the chromatin landscape during neurogenesis. Cell Rep. 10, 1544–1556 (2015).
Gerber, A. N., Klesert, T. R., Bergstrom, D. A. & Tapscott, S. J. Two domains of MyoD mediate transcriptional activation of genes in repressive chromatin: a mechanism for lineage determination in myogenesis. Genes Dev. 11, 436–450 (1997).
Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).
Fu, Y. et al. STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus. Nat. Commun. 11, 4882 (2020).
Desanlis, I. et al. HOX13-dependent chromatin accessibility underlies the transition towards the digit development program. Nat. Commun. 11, 2491 (2020).
Yu, B. et al. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell 13, 328–340 (2013).
Pfisterer, U. et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl Acad. Sci. USA 108, 10343–10348 (2011).
Son, E. Y. et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9, 205–218 (2011).
Marro, S. et al. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9, 374–382 (2011).
Lujan, E., Chanda, S., Ahlenius, H., Südhof, T. C. & Wernig, M. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc. Natl Acad. Sci. USA 109, 2527–2532 (2012).
Szabo, E. et al. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468, 521–526 (2010).
Pereira, C. F. et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell 13, 205–218 (2013).
Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).
Yamamoto, K. et al. Direct conversion of human fibroblasts into functional osteoblasts by defined factors. Proc. Natl Acad. Sci. USA 112, 6152–6157 (2015).
Swinstead, E. E., Paakinaho, V., Presman, D. M. & Hager, G. L. Pioneer factors and ATP-dependent chromatin remodeling factors interact dynamically: a new perspective: multiple transcription factors can effect chromatin pioneer functions through dynamic interactions with ATP-dependent chromatin remodeling factors. Bioessays 38, 1150–1157 (2016).
Festuccia, N. et al. Mitotic binding of Esrrb marks key regulatory regions of the pluripotency network. Nat. Cell Biol. 18, 1139–1148 (2016).
Kadauke, S. et al. Tissue-specific mitotic bookmarking by hematopoietic transcription factor GATA1. Cell 150, 725–737 (2012).
Caravaca, J. M. et al. Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Genes Dev. 27, 251–260 (2013).
Deluz, C. et al. A role for mitotic bookmarking of SOX2 in pluripotency and differentiation. Genes Dev. 30, 2538–2550 (2016).
Festuccia, N. et al. Transcription factor activity and nucleosome organization in mitosis. Genome Res. 29, 250–260 (2019).
Soares, M. A. F. et al. Hierarchical reactivation of transcription during mitosis-to-G1 transition by Brn2 and Ascl1 in neural stem cells. Genes Dev. 35, 1020–1034 (2021).
Acknowledgements
Work in the authors’ laboratory was funded by a Foundation grant (FRN-154297) from the Canadian Institutes of Health.
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Glossary
- Pioneer factors
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Transcription factors with the unique ability to bind DNA target sites within closed chromatin, typically regulatory elements such as enhancers with undetectable levels of active-chromatin modifications before pioneer action.
- Epigenetic memory
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The processes and mechanisms responsible for maintenance of chromatin structure and gene activity status, either as heterochromatin or as active chromatin. The core epigenetic-memory mark of inactive chromatin is DNA CpG methylation.
- Transcriptional memory
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The processes and mechanisms by which the first round of gene transcription remodels the epigenome for quicker transcription upon subsequent reactivation.
- DNA footprinting
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Techniques to reveal the presence of DNA-bound proteins through their impairment of access to DNA.
- Basic helix–loop–helix
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(bHLH). Structure of a DNA-binding domain of a family of transcription factors.
- Pioneer factor-resistant sites
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Chromatin recruitment sites typically showing weak pioneer binding that does not produce any change in chromatin organization.
- Melanotrope cell
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Endocrine cell of the pituitary intermediate lobe that secretes the pro-opiomelanocortin-derived hormone α-melanotropin.
- Constitutive heterochromatin
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Part of the genome in which the chromatin is permanently ‘closed’ and transcriptionally inactive; typically marked by trimethylated histone H3Lys9 (H3K9me3).
- Facultative heterochromatin
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Part of the genome in which transcriptionally inactive chromatin is amenable to cell type-specific activation; enriched in dimethylated histone H3 Lys9 (H3K9me2).
- Topologically associating domains
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(TADs). Chromatin domains that are partially insulated from flanking domains by boundaries that contain convergent binding sites for CCCTC-binding factor (CTCF).
- Assay for transposase-accessible chromatin with high-throughput sequencing
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(ATAC–seq). Technique to map chromatin accessibility based on insertion frequencies of a transposable element within accessible DNA.
- Active enhancers
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Enhancers marked by nucleosome depletion, DNA accessibility, bimodal distribution of the active-chromatin modifications monomethylated histone H3 Lys4 (H3K4me1) and acetylated histone H3 Lys27 (H3K27ac) and the presence of the co-activator p300.
- Primed enhancer
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An enhancer with low levels of the epigenetic mark of activity monomethylated histone H3 Lys4 (H3K4me1) and DNA accessibility and no nucleosome depletion.
- MNase–seq
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A technique to visualize nucleosome positioning that uses partial DNA digestion with micrococcal nuclease 1 and high-throughput sequencing.
- Nuclear receptors
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Transcription factors that are activated upon binding of cognate ligands and translocate into the nucleus.
- Mediator
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A protein complex of about 30 proteins that integrates the inputs of enhancer-bound transcription factors to activate RNA polymerase II (Pol II) at promoters.
- Corticotrope cell
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Endocrine cell of the pituitary anterior lobe that secretes the pro-opiomelanocortin-derived hormone adrenocorticotropin.
- Cell replacement therapies
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Therapies designed to replace deficient cells by competent cells, such as pancreatic β-cells in diabetes or dopaminergic neurons in Parkinson disease. This replacement could be achieved by transplantation of reprogrammed cells or by reprograming cells in vivo.
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Balsalobre, A., Drouin, J. Pioneer factors as master regulators of the epigenome and cell fate. Nat Rev Mol Cell Biol 23, 449–464 (2022). https://doi.org/10.1038/s41580-022-00464-z
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DOI: https://doi.org/10.1038/s41580-022-00464-z
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