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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.

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Fig. 1: The pioneer action.
Fig. 2: Cooperation between pioneer and non-pioneer transcription factors.
Fig. 3: Primed enhancers as a mechanism of epigenetic and transcriptional memories.
Fig. 4: Pioneer and non-pioneer transcription factors cooperate for specification and determination of cell fates.

References

  1. Iwafuchi-Doi, M. & Zaret, K. S. Cell fate control by pioneer transcription factors. Development 143, 1833–1837 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Mayran, A. & Drouin, J. Pioneer transcription factors shape the epigenetic landscape. J. Biol. Chem. 293, 13795–13804 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Larson, E. D., Marsh, A. J. & Harrison, M. M. Pioneering the developmental frontier. Mol. Cell 81, 1640–1650 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Stewart-Morgan, K. R., Petryk, N. & Groth, A. Chromatin replication and epigenetic cell memory. Nat. Cell Biol. 22, 361–371 (2020).

    CAS  PubMed  Article  Google Scholar 

  5. 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).

    CAS  PubMed  Article  Google Scholar 

  6. Donaghey, J. et al. Genetic determinants and epigenetic effects of pioneer-factor occupancy. Nat. Genet. 50, 250–258 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Mayran, A. et al. Pioneer factor Pax7 deploys a stable enhancer repertoire for specification of cell fate. Nat. Genet. 50, 259–269 (2018).

    CAS  PubMed  Article  Google Scholar 

  8. Barozzi, I. et al. Coregulation of transcription factor binding and nucleosome occupancy through DNA features of mammalian enhancers. Mol. Cell 54, 844–857 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 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).

    CAS  PubMed  Article  Google Scholar 

  10. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 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).

    CAS  PubMed  Article  Google Scholar 

  14. 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).

    CAS  PubMed  Article  Google Scholar 

  15. Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–837 (2013).

    CAS  PubMed  Article  Google Scholar 

  16. Aydin, B. & Mazzoni, E. O. Cell reprogramming: the many roads to success. Annu. Rev. Cell Dev. Biol. 35, 433–452 (2019).

    CAS  PubMed  Article  Google Scholar 

  17. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Adams, E. J. et al. FOXA1 mutations alter pioneering activity, differentiation and prostate cancer phenotypes. Nature 571, 408–412 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Hankey, W., Chen, Z. & Wang, Q. Shaping chromatin states in prostate cancer by pioneer transcription factors. Cancer Res. 80, 2427–2436 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Sun, Y. et al. HOXA9 reprograms the enhancer landscape to promote leukemogenesis. Cancer Cell 34, 643–658.e5 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Gualdi, R. et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 10, 1670–1682 (1996).

    CAS  PubMed  Article  Google Scholar 

  23. Zaret, K. S. & Mango, S. E. Pioneer transcription factors, chromatin dynamics, and cell fate control. Curr. Opin. Genet. Dev. 37, 76–81 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Zhu, F. et al. The interaction landscape between transcription factors and the nucleosome. Nature 562, 76–81 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 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).

    CAS  PubMed  Article  Google Scholar 

  27. Michael, A. K. et al. Mechanisms of OCT4-SOX2 motif readout on nucleosomes. Science 368, 1460–1465 (2020).

    CAS  PubMed  Article  Google Scholar 

  28. Tanaka, H. et al. Interaction of the pioneer transcription factor GATA3 with nucleosomes. Nat. Commun. 11, 4136 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Fernandez Garcia, M. et al. Structural features of transcription factors associating with nucleosome binding. Mol. Cell 75, 921–932.e6 (2019).

    CAS  PubMed  Article  Google Scholar 

  30. Soufi, A. et al. Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 161, 555–568 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Mayran, A. et al. Pioneer and nonpioneer factor cooperation drives lineage specific chromatin opening. Nat. Commun. 10, 3807 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Nicetto, D. et al. H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification. Science 363, 294–297 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Koche, R. P. et al. Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 8, 96–105 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Hildebrand, E. M. & Dekker, J. Mechanisms and functions of chromosome compartmentalization. Trends Biochem. Sci. 45, 385–396 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Poleshko, A. et al. Genome-nuclear lamina interactions regulate cardiac stem cell lineage restriction. Cell 171, 573–587.e14 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Stadhouders, R. et al. Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nat. Genet. 50, 238–249 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 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).

    Article  Google Scholar 

  40. Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Li, R. et al. Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming. Genes Dev. 32, 96–111 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Wapinski, O. L. et al. Rapid chromatin switch in the direct reprogramming of fibroblasts to neurons. Cell Rep. 20, 3236–3247 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. King, H. A., Trotter, K. W. & Archer, T. K. Chromatin remodeling during glucocorticoid receptor regulated transactivation. Biochim. Biophys. Acta 1819, 716–726 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  48. Takaku, M. et al. GATA3-dependent cellular reprogramming requires activation-domain dependent recruitment of a chromatin remodeler. Genome Biol. 17, 36 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Gao, R. et al. Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate. Cell Res. 29, 486–501 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  51. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Alver, B. H. et al. The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers. Nat. Commun. 8, 14648 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  53. Jindal, G. A. & Farley, E. K. Enhancer grammar in development, evolution, and disease: dependencies and interplay. Dev. Cell 56, 575–587 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Huang, P. et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386–389 (2011).

    CAS  PubMed  Article  Google Scholar 

  55. Sekiya, S. & Suzuki, A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475, 390–393 (2011).

    CAS  PubMed  Article  Google Scholar 

  56. Lee, K. et al. FOXA2 is required for enhancer priming during pancreatic differentiation. Cell Rep. 28, 382–393.e7 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 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).

    CAS  PubMed  Article  Google Scholar 

  59. Lupien, M. et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132, 958–970 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Wang, Q. et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138, 245–256 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Voss, T. C. et al. Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146, 544–554 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Swinstead, E. E. et al. Steroid receptors reprogram FoxA1 occupancy through dynamic chromatin transitions. Cell 165, 593–605 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 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).

    CAS  PubMed  Article  Google Scholar 

  67. Jacobs, J. et al. The transcription factor Grainy head primes epithelial enhancers for spatiotemporal activation by displacing nucleosomes. Nat. Genet. 50, 1011–1020 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. Escobar, T. M. et al. Active and repressed chromatin domains exhibit distinct nucleosome segregation during DNA replication. Cell 179, 953–963.e11 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Busslinger, M., Hurst, J. & Flavell, R. A. DNA methylation and the regulation of globin gene expression. Cell 34, 197–206 (1983).

    CAS  PubMed  Article  Google Scholar 

  72. Bird, A. P. CpG-rich islands and the function of DNA methylation. Nature 321, 209–213 (1986).

    CAS  PubMed  Article  Google Scholar 

  73. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Jadhav, U. et al. Extensive recovery of embryonic enhancer and gene memory stored in hypomethylated enhancer DNA. Mol. Cell 74, 542–554.e5 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Reizel, Y. et al. FoxA-dependent demethylation of DNA initiates epigenetic memory of cellular identity. Dev. Cell 56, 602–612.e4 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Sardina, J. L. et al. Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell 23, 727–741.e9 (2018).

    CAS  PubMed  Article  Google Scholar 

  78. Hahn, M. A. et al. Reprogramming of DNA methylation at NEUROD2-bound sequences during cortical neuron differentiation. Sci. Adv. 5, eaax0080 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Lio, C. J. et al. TET methylcytosine oxidases: new insights from a decade of research. J. Biosci. 45, 21 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Yang, Y. A. et al. FOXA1 potentiates lineage-specific enhancer activation through modulating TET1 expression and function. Nucleic Acids Res. 44, 8153–8164 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Zhang, Y. et al. Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nat. Genet. 48, 1003–1013 (2016).

    CAS  PubMed  Article  Google Scholar 

  82. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 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).

    Article  CAS  Google Scholar 

  84. 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).

    PubMed Central  Article  CAS  Google Scholar 

  85. Dufourt, J. et al. Temporal control of gene expression by the pioneer factor Zelda through transient interactions in hubs. Nat. Commun. 9, 5194 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. Tu, W. J. et al. Priming of transcriptional memory responses via the chromatin accessibility landscape in T cells. Sci. Rep. 7, 44825 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Luo, C. et al. Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons. eLife 8, e40197 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  90. D’Urso, A. et al. Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory. eLife 5, e16691 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  91. Horisawa, K. et al. The dynamics of transcriptional activation by hepatic reprogramming factors. Mol. Cell 79, 660–676.e8 (2020).

    CAS  PubMed  Article  Google Scholar 

  92. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Hsu, H. T. et al. Recruitment of RNA polymerase II by the pioneer transcription factor PHA-4. Science 348, 1372–1376 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 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).

    CAS  PubMed  Article  Google Scholar 

  95. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 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).

    PubMed  PubMed Central  Article  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Serandour, A. A. et al. Epigenetic switch involved in activation of pioneer factor FOXA1-dependent enhancers. Genome Res. 21, 555–565 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Holtzinger, A. & Evans, T. Gata4 regulates the formation of multiple organs. Development 132, 4005–4014 (2005).

    CAS  PubMed  Article  Google Scholar 

  108. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Lin, H. & Grosschedl, R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–267 (1995).

    CAS  PubMed  Article  Google Scholar 

  112. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Johanson, T. M. et al. Transcription-factor-mediated supervision of global genome architecture maintains B cell identity. Nat. Immunol. 19, 1257–1264 (2018).

    CAS  PubMed  Article  Google Scholar 

  114. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Johnson, J. L. et al. Lineage-determining transcription factor TCF-1 initiates the epigenetic identity of T cells. Immunity 48, 243–257.e10 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Weber, B. N. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63–68 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 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).

    CAS  PubMed  Article  Google Scholar 

  120. Pulichino, A. M. et al. Tpit determines alternate fates during pituitary cell differentiation. Genes Dev. 17, 738–747 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Pulichino, A. M. et al. Human and mouse Tpit gene mutations cause early onset pituitary ACTH deficiency. Genes Dev. 17, 711–716 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Luna-Zurita, L. et al. Complex interdependence regulates heterotypic transcription factor distribution and coordinates cardiogenesis. Cell 164, 999–1014 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. He, A. et al. Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease. Nat. Commun. 5, 4907 (2014).

    CAS  PubMed  Article  Google Scholar 

  124. 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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. Gurdon, J. B. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962).

    CAS  PubMed  Google Scholar 

  126. Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007).

    CAS  PubMed  Article  Google Scholar 

  127. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  PubMed  Article  Google Scholar 

  128. Chronis, C. et al. Cooperative binding of transcription factors orchestrates reprogramming. Cell 168, 442–459.e20 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Wapinski, O. L. et al. Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155, 621–635 (2013).

    CAS  PubMed  Article  Google Scholar 

  130. 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).

    CAS  PubMed  Article  Google Scholar 

  131. Vierbuchen, T. et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Pataskar, A. et al. NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program. EMBO J. 35, 24–45 (2016).

    CAS  PubMed  Article  Google Scholar 

  133. Davis, R. L., Weintraub, H. & Lassar, A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51, 987–1000 (1987).

    CAS  PubMed  Article  Google Scholar 

  134. Tapscott, S. J. et al. MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts. Science 242, 405–411 (1988).

    CAS  PubMed  Article  Google Scholar 

  135. Lee, Q. Y. et al. Pro-neuronal activity of Myod1 due to promiscuous binding to neuronal genes. Nat. Cell Biol. 22, 401–411 (2020).

    CAS  PubMed  Article  Google Scholar 

  136. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Zhou, Q. & Melton, D. A. Pancreas regeneration. Nature 557, 351–358 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 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).

    CAS  PubMed  Article  Google Scholar 

  139. Carroll, J. S. et al. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38, 1289–1297 (2006).

    CAS  PubMed  Article  Google Scholar 

  140. Pomerantz, M. M. et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat. Genet. 47, 1346–1351 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. Zhou, S. et al. Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer. Nat. Commun. 11, 441 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 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).

    CAS  PubMed  Article  Google Scholar 

  145. Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 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).

    CAS  PubMed  Article  Google Scholar 

  147. 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).

    CAS  PubMed  Article  Google Scholar 

  148. Hatta, M. & Cirillo, L. A. Chromatin opening and stable perturbation of core histone:DNA contacts by FoxO1. J. Biol. Chem. 282, 35583–35593 (2007).

    CAS  PubMed  Article  Google Scholar 

  149. So, C. W. & Cleary, M. L. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood 101, 633–639 (2003).

    CAS  PubMed  Article  Google Scholar 

  150. Young, J. M. et al. DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet. 9, e1003947 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. Lim, K. R. Q., Nguyen, Q. & Yokota, T. DUX4 signalling in the pathogenesis of facioscapulohumeral muscular dystrophy. Int. J. Mol. Sci. 21, 729 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  152. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Minderjahn, J. et al. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1. Nat. Commun. 11, 402 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Raposo, A. et al. Ascl1 coordinately regulates gene expression and the chromatin landscape during neurogenesis. Cell Rep. 10, 1544–1556 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 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).

    CAS  PubMed  Article  Google Scholar 

  156. Biddie, S. C. et al. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43, 145–155 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Fu, Y. et al. STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus. Nat. Commun. 11, 4882 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Desanlis, I. et al. HOX13-dependent chromatin accessibility underlies the transition towards the digit development program. Nat. Commun. 11, 2491 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. Yu, B. et al. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell 13, 328–340 (2013).

    CAS  PubMed  Article  Google Scholar 

  160. Pfisterer, U. et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl Acad. Sci. USA 108, 10343–10348 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Son, E. Y. et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9, 205–218 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Marro, S. et al. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9, 374–382 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. Szabo, E. et al. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature 468, 521–526 (2010).

    CAS  PubMed  Article  Google Scholar 

  165. Pereira, C. F. et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell 13, 205–218 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. Ieda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  167. Yamamoto, K. et al. Direct conversion of human fibroblasts into functional osteoblasts by defined factors. Proc. Natl Acad. Sci. USA 112, 6152–6157 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Festuccia, N. et al. Mitotic binding of Esrrb marks key regulatory regions of the pluripotency network. Nat. Cell Biol. 18, 1139–1148 (2016).

    CAS  PubMed  Article  Google Scholar 

  170. Kadauke, S. et al. Tissue-specific mitotic bookmarking by hematopoietic transcription factor GATA1. Cell 150, 725–737 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Caravaca, J. M. et al. Bookmarking by specific and nonspecific binding of FoxA1 pioneer factor to mitotic chromosomes. Genes Dev. 27, 251–260 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. Deluz, C. et al. A role for mitotic bookmarking of SOX2 in pluripotency and differentiation. Genes Dev. 30, 2538–2550 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Festuccia, N. et al. Transcription factor activity and nucleosome organization in mitosis. Genome Res. 29, 250–260 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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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

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

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

The processes and mechanisms by which the first round of gene transcription remodels the epigenome for quicker transcription upon subsequent reactivation.

DNA footprinting

Techniques to reveal the presence of DNA-bound proteins through their impairment of access to DNA.

Basic helix–loop–helix

(bHLH). Structure of a DNA-binding domain of a family of transcription factors.

Pioneer factor-resistant sites

Chromatin recruitment sites typically showing weak pioneer binding that does not produce any change in chromatin organization.

Melanotrope cell

Endocrine cell of the pituitary intermediate lobe that secretes the pro-opiomelanocortin-derived hormone α-melanotropin.

Constitutive heterochromatin

Part of the genome in which the chromatin is permanently ‘closed’ and transcriptionally inactive; typically marked by trimethylated histone H3Lys9 (H3K9me3).

Facultative heterochromatin

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

(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

(ATAC–seq). Technique to map chromatin accessibility based on insertion frequencies of a transposable element within accessible DNA.

Active enhancers

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

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

A technique to visualize nucleosome positioning that uses partial DNA digestion with micrococcal nuclease 1 and high-throughput sequencing.

Nuclear receptors

Transcription factors that are activated upon binding of cognate ligands and translocate into the nucleus.

Mediator

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

Endocrine cell of the pituitary anterior lobe that secretes the pro-opiomelanocortin-derived hormone adrenocorticotropin.

Cell replacement therapies

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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