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Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
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SUMMARY Pioneer transcription factors (TFs) access silent chromatin and initiate cell fate changes, using diverse types of DNA binding domains (DBDs). FoxA, the paradigm pioneer TF, has a winged helix DBD that resembles linker histone and thereby binds its target sites on nucleosomes and in compacted chromatin. Herein we compare the nucleosome and chromatin targeting activities of Oct4 (POU DBD), Sox2 (HMG box DBD), Klf4 (zinc finger DBD), and c-Myc (bHLH DBD), which together reprogram somatic cells to pluripotency. Purified Oct4, Sox2, and Klf4 proteins can bind nucleosomes in vitro, and in vivo they preferentially target silent sites enriched for nucleosomes. Pioneer activity relates simply to the ability of a given DBD to target partial motifs displayed on the nucleosome surface. Such partial motif recognition can occur by coordinate binding between factors. Our findings provide insight into how pioneer factors can target naïve chromatin sites.
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“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 [60]
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“We show here that JGES reprogramming differs markedly from the classic Yamanaka factors OSKM in that JGES relies on Sall4 to engage endogenous NuRD to close open chromatin in MEFs while OSKM relies on pioneering factors to open chromatin in MEFs10,60.”
From The NuRD complex cooperates with SALL4 to orchestrate reprogramming (2023) · cites this paper as [60]
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“The pluripotency factors OCT4, SOX2, and KLF4, when acting as pioneer TFs, bind nucleosomes in vitro by targeting partial and degenerate DNA motifs displayed on the nucleosome surface (64).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [64]
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“which has also been observed at sites of nucleosomal binding by the pioneer and pluripotency factor SOX2 (64).”
From SOX9 reprograms endothelial cells by altering the chromatin landscape (2022) · cites this paper as [64]
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“In contrast with the OSK factors, which function synergistically as pioneer factors during reprogramming, MYC (Fig. 1d) does not exert this function 55 .”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [55]
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“For example, a handful pioneer TFs (such as OCT4, SOX2 and KLF4) were shown to bind only partial motifs displayed on the nucleosome surface107.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [107]
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BackgroundThe Hierarchy of Transcriptional Activation: From Enhancer to Promoter
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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
“Other TFs involved in reprogramming of somatic cells to pluripotency such as Oct4, Sox2, and Klf4, also function as pioneer factors utilizing unique adaptations of their DNA recognition surfaces to accommodate nucleosome structure, which likely represents a common genome interrogation mechanism of the pioneer class [1…”
BackgroundPoli, V., Fagnocchi, L., Fasciani, A., Cherubini, A., Mazzoleni, S., Ferrillo, S., Miluzio, A., Gaudioso, G., Vaira, V., Turdo, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03264-2 · Cited by 154
Transcription Factors and DNA Play Hide and Seek
Suter, D. M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.03.003 · Cited by 143
Widespread Mitotic Bookmarking by Histone Marks and Transcription Factors in Pluripotent Stem Cells
Liu, Y., Pelham‐Webb, B., Giammartino, D. C. D., Li, J., Kim, D., Kita, K., Saiz, N., Garg, V., Doane, A. S., Giannakakou, P., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.04.067 · Cited by 141
“In agreementwith these results,motif scanninganalysesusingeither the ESC or the G1E bookmarked H3K27ac enhancer peaks enriched for binding sites recognized by the master regulators of each cell type, such as OSN (OCT4-SOX2-NANOG) and ESRRB or GATA1, respectively (Figure S2E; Table S2).”
BackgroundInfluentialTwo-Parameter Mobility Assessments Discriminate Diverse Regulatory Factor Behaviors in Chromatin
Lerner, J., Gomez-Garcia, P. A., McCarthy, R. L., Liu, Z., Lakadamyali, M., & Zaret, K. S. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.05.036 · Cited by 110
“, 2019) show that the genomic occupancy by transcription factor is sensitive to the local chromatin context (Soufi et al., 2015).”
BackgroundSelf-citationBalakrishnan, A., Belfiore, L., Chu, T., Fleming, T., Midha, R., Biernaskie, J. A., & Schuurmans, C. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.608442 · Cited by 149
“Similarly, Olig2 is incorporated in oligodendrocyte reprogramming protocols for its function as a pioneer factor (Yu et al., 2013), as are Sox family genes (Soufi et al., 2015; Hou et al., 2017).”
BackgroundChromatin Control of Developmental Dynamics and Plasticity
Perino, M., & Veenstra, G. J. C. (2016) · Developmental Cell · doi:10.1016/j.devcel.2016.08.004 · Cited by 134
Rapid Chromatin Switch in the Direct Reprogramming of Fibroblasts to Neurons
Wapinski, O. L., Lee, Q. Y., Chen, A. C., Li, R., Corces, M. R., Ang, C. E., Treutlein, B., Xiang, C., Baubet, V., Suchy, F. P., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.011 · Cited by 147
“, 2012) and DNA elements preferentially pioneered contain only parts of the canonical binding motifs (Soufi et al., 2015).”
Pioneer and nonpioneer factor cooperation drives lineage specific chromatin opening
Mayran, A., Sochodolsky, K., Khetchoumian, K., Harris, J., Gauthier, Y., Bemmo, A., Balsalobre, A., & Drouin, J. (2019) · Nature Communications · doi:10.1038/s41467-019-11791-9 · Cited by 141
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LEAFY is a pioneer transcription factor and licenses cell reprogramming to floral fate
Jin, R., Klasfeld, S., Zhu, Y., García, M. F., Xiao, J. Y., Han, S., Konkol, A., & Wagner, D. (2021) · Nature Communications · doi:10.1038/s41467-020-20883-w · Cited by 134
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Gaskill, M. M., Gibson, T. J., Larson, E. D., & Harrison, M. M. (2021) · eLife · doi:10.7554/elife.66668 · Cited by 136
Presnell, J. S., Schnitzler, C. E., & Browne, W. E. (2015) · Genome Biology and Evolution · doi:10.1093/gbe/evv141 · Cited by 119
Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei
Fasci, D., van Ingen, H., Scheltema, R. A., & Heck, A. J. R. (2018) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra118.000924 · Cited by 133
“Hn-RNPK can act both as transcriptional co-activator or repressor and plays a role in the transcriptional regulation of p53 after DNA damage (66, 67).”
BackgroundInfluentialPioneer factors: roles and their regulation in development
Barral, A., & Zaret, K. S. (2023) · Trends in Genetics · doi:10.1016/j.tig.2023.10.007 · Cited by 135
Self-citationThe Sox2 transcription factor binds RNA
Holmes, Z. E., Hamilton, D. J., Hwang, T., Parsonnet, N. V., Rinn, J. L., Wuttke, D. S., & Batey, R. (2020) · Nature Communications · doi:10.1038/s41467-020-15571-8 · Cited by 136
Knaupp, A. S., Buckberry, S., Pflueger, J., Lim, S. M., Ford, E., Larcombe, M. R., Rossello, F. J., de Mendoza, A., Alaei, S., Firas, J., et al. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.11.007 · Cited by 127
The emerging roles of Oct4 in tumor-initiating cells
Wang, Y., & Herlyn, M. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00212.2015 · Cited by 122
“Purified Oct4 proteins can bind nucleosomes in vitro, and in vivo they preferentially target silent sites enriched for nucleosomes thereby acting as a pioneer transcription factor during cell reprogramming (90, 91).”
BackgroundLi, Z., Martin, M., Zhang, J., Huang, H., Bai, L., Zhang, J., Kang, J., He, M., Li, J., Maurya, M. R., et al. (2017) · Circulation · doi:10.1161/circulationaha.117.027462 · Cited by 124
Hormone-dependent control of developmental timing through regulation of chromatin accessibilityPreprint
Uyehara, C. M., Nystrom, S. L., Niederhuber, M. J., Leatham-Jensen, M., Ma, Y., Buttitta, L., & McKay, D. J. (2017) · Genes & Development · doi:10.1101/gad.298182.117 · Cited by 119
“More recently, the master transcription factors of embryonic stem cell identity — Oct4, Sox2, and Klf4 — were shown to have pio-neering activity during induction of pluripotency in induced pluripotency stem (iPS) cells (Soufi et al. 2015).”
Liu, Z., & Kraus, W. L. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.017 · Cited by 113
“, FoxA1) function as pioneer TFs for genome accessibility has been debated in the recent literature (Franco et al., 2015; Iwafuchi-Doi et al., 2016; Soufi et al., 2015; Swinstead et al., 2016; Zaret et al., 2016).”
BackgroundInfluentialMolecular basis for the genome engagement by Sox proteins
Hou, L., Srivastava, Y., & Jauch, R. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.08.005 · Cited by 113
“t early stages of iPSC generation [134,135].”
Lukoseviciute, M., Gavriouchkina, D., Williams, R. M., Hochgreb-Hagele, T., Senanayake, U., Chong-Morrison, V., Thongjuea, S., Repapi, E., Mead, A., & Sauka-Spengler, T. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.11.009 · Cited by 109
Cooperation between bHLH transcription factors and histones for DNA access
Michael, A. K., Stoos, L., Crosby, P., Eggers, N., Nie, X. Y., Makasheva, K. A., Minnich, M., Healy, K. L., Weiss, J., Kempf, G., et al. (2023) · Nature · doi:10.1038/s41586-023-06282-3 · Cited by 116
Mechanisms of Binding Specificity among bHLH Transcription Factors
de Martin, X., Sodaei, R., & Santpere, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179150 · Cited by 118
“[98] associated the pioneer characteristics of some transcription factors to the length of the basic helix-1 and to their ability to bind centrally degenerate motifs in the surface of the nucleosome [98].”
BackgroundResultInfluentialContinued Activity of the Pioneer Factor Zelda Is Required to Drive Zygotic Genome Activation
McDaniel, S. L., Gibson, T. J., Schulz, K. N., García, M. F., Nevil, M., Jain, S. U., Lewis, P. W., Zaret, K. S., & Harrison, M. M. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.014 · Cited by 113
“The ability to bind DNA even when it is wrapped around histones in nucleosomes likely enables Oct4 to bind closed chromatin and initiate reprogramming (Soufi et al., 2015).”
Self-citationHistone modifications regulate pioneer transcription factor cooperativity
Sinha, K. K., Bilokapić, S., Du, Y., Malik, D., & Halić, M. (2023) · Nature · doi:10.1038/s41586-023-06112-6 · Cited by 122
Chromatin expansion microscopy reveals nanoscale organization of transcription and chromatin
Pownall, M. E., Miao, L., Vejnar, C. E., M’Saad, O., Sherrard, A., Frederick, M. A., Benitez, M. D. J., Boswell, C. W., Zaret, K. S., Bewersdorf, J., et al. (2023) · Science · doi:10.1126/science.ade5308 · Cited by 110
Self-citationBeyond proneural: emerging functions and regulations of proneural proteins
Guillemot, F., & Hassan, B. A. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2016.11.011 · Cited by 101
Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate
Gao, R., Liang, X., Cheedipudi, S. M., Cordero, J., Jiang, X. X., Zhang, Q., Caputo, L., Günther, S., Kuenne, C. T., Ren, Y., et al. (2019) · Cell Research · doi:10.1038/s41422-019-0168-1 · Cited by 106
Velasco, S., Ibrahim, M. M., Kakumanu, A., Garipler, G., Aydin, B., Al-Sayegh, M. A., Hirsekorn, A., Abdul-Rahman, F., Satija, R., Ohler, U., et al. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2016.11.006 · Cited by 111
“In a small percentage of the cells, the OSKM factors have the ability to bind to repressed chromatin domains and activate pluripotency gene expression (Soufi et al., 2012, 2015).”
BackgroundStefano, B. D., Collombet, S., Jakobsen, J. S., Wierer, M., Sardina, J. L., Lackner, A., Stadhouders, R., Segura-Morales, C., Francesconi, M., Limone, F., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3326 · Cited by 106
Chromatin remodeling in bovine embryos indicates species-specific regulation of genome activation
Halstead, M. M., Ma, X., Zhou, C., Schultz, R. M., & Ross, P. J. (2020) · Nature Communications · doi:10.1038/s41467-020-18508-3 · Cited by 109
Foxa2 identifies a cardiac progenitor population with ventricular differentiation potential
Bardot, E., Calderon, D., Santoriello, F. J., Han, S., Cheung, K., Jadhav, B., Burtscher, I., Artap, S. T., Jain, R., Epstein, J. A., et al. (2017) · Nature Communications · doi:10.1038/ncomms14428 · Cited by 101
Systematic Study of Nucleosome-Displacing Factors in Budding Yeast
Yan, C. Y. I., Chen, H., & Bai, L. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.06.017 · Cited by 104
“For PFs, it was proposed that the pioneer activities rely on special DBD structures that allow them to bind nucleosome with high affinity (Soufi et al., 2015; Zaret and Carroll, 2011).”
Mueller, B., Mieczkowski, J., Kundu, S., Wang, P., Sadreyev, R., Tolstorukov, M. Y., & Kingston, R. E. (2017) · Genes & Development · doi:10.1101/gad.293118.116 · Cited by 100
“…certain TSSs, transiently destabilized nucleosomes during viral induction of gene expression, and retention of nucleosomes in enhancer regions bound by FoxA and other factors (Xi et al. 2011; Knight et al. 2014; Sexton et al. 2014; Teif et al. 2014; Soufi et al. 2015; Iwafuchi-Doi et al. 2016).”
BackgroundChromatin Fiber Invasion and Nucleosome Displacement by the Rap1 Transcription Factor
Mivelaz, M., Cao, A.-M., Kubik, S., Zencir, S., Hovius, R., Boichenko, I., Stachowicz, A. M., Kurat, C. F., Shore, D., & Fierz, B. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.10.025 · Cited by 99
“A common feature of DNA binding domains (DBDs) of pTFs is their ability to bind partial sequence motifs displayed on nucleosomes (Soufi et al., 2015).”
BackgroundInteraction of the pioneer transcription factor GATA3 with nucleosomes
Tanaka, H., Takizawa, Y., Takaku, M., Kato, D., Kumagawa, Y., Grimm, S. A., Wade, P. A., & Kurumizaka, H. (2020) · Nature Communications · doi:10.1038/s41467-020-17959-y · Cited by 99
Metadata
- Authors
- Soufi, A., Garcia, M. F., Jaroszewicz, A., Osman, N., Pellegrini, M., & Zaret, K. S.
- Affiliations
- University of Pennsylvania (US)
- University of California, Los Angeles (US)
- Corresponding author
- Zaret, Kenneth S.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 161
- Issue
- 3
- Pages
- 555-568
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4409934
- OpenAlex
- W1971451591
- Semantic Scholar
- 0a23a104294ce4318a90a1c70248de6cc65b2f1f
- Cited by
- 780
- References
- 85
- Citations by year
- 2026: 54 · 2025: 57 · 2024: 67 · 2023: 78 · 2022: 82 · 2021: 89 · 2020: 77 · 2019: 66 · 2018: 72 · 2017: 59 · 2016: 54 · 2015: 23
- FWCI
- 30.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (T32HG002536)
- National Institute of General Medical Sciences (P01GM099134)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- pioneer transcription factors, nucleosome binding, DNA-binding domain, chromatin accessibility, cellular reprogramming, pluripotency, Oct4, SOX2, KLF4, c-Myc, HMG box, bHLH, zinc finger, silent chromatin, chromatin remodeling
- MeSH terms
- Kruppel-Like Factor 4, Amino Acid Sequence, DNA, Fibroblasts, Humans, Models, Molecular, Nucleosomes, Transcription Factors, Sequence Alignment, Protein Structure, Tertiary, Octamer Transcription Factor-3, Cell Dedifferentiation, Induced Pluripotent Stem Cells, Nucleotide Motifs, Cellular Reprogramming
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