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Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
Open accessAbstract
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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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]
In the citing paper
“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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Citations
Cites
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“However, a select group of transcription factors (TFs) known as pioneer factors have the combined ability to access their target sites in silent chromatin and initiate cell-fate changes (Iwafuchi-Doi and Zaret, 2014; Zaret and Carroll, 2011).”
Self-citationTranscriptional Amplification in Tumor Cells with Elevated c-Myc
Lin, C. Y., Lovén, J., Rahl, P. B., Paranal, R. M., Burge, C. B., Bradner, J. E., Lee, T. I., & Young, R. A. (2012) · Cell · doi:10.1016/j.cell.2012.08.026 · Cited by 1,543 · cited 2×
“However, nucleosome-depleted targets were enriched for a less degenerate E-box motif that we and others have previously reported to be associated with c-Myc binding at enhancers (Lin et al., 2012; Nie et al., 2012; Soufi et al., 2012) (Figure 5B, single arrowhead in bottom panel).”
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Proliferation history and transcription factor levels drive direct conversion
Wang, N., Lende-Dorn, B. A., Beitz, A. M., Han, P., Adewumi, H. O., O’Shea, T. M., & Galloway, K. E. (2023) · Cell Systems · doi:10.1016/j.cels.2025.101205 · Cited by 19
Orchestration of pluripotent stem cell genome reactivation during mitotic exit
Placzek, S., Vanzan, L., Deluz, C., & Suter, D. M. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115486 · Cited by 7
Izsvák, Z., Ma, J., Singh, M., & Hurst, L. D. (2025) · Mobile DNA · doi:10.1186/s13100-025-00361-0 · Cited by 11
“Given that TRIM28/KAP1 does not seem to be the primary suppressor of HERVH in human ESCs, it has been proposed that pioneer factor KLF4 [124] prevents TRIM28/KAP1 binding and instead recruit additional pluripotency factors, as well as the E1A-binding protein p300 histone acetyltransferase, to HERVH…”
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Deciphering Allosteric Modulation of Cancer-Associated Histone Missense Mutations
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“For example, among ‘Yamanaka-TFs’, Oct4, Sox2 and Klf4 are known to act by cis-reprogramming as pioneer TFs, whereas c-Myc only binds to opened chromatin to act by trans-reprogramming as secondary enhancer, which is not necessary for generating iPSCs.(18) Pioneer TFs drive somatic cells to be multi-potent cells that c…”
BackgroundChromatin architecture reorganization during somatic cell reprogramming
Zhao, K., Wang, M., Gao, S., & Chen, J. (2021) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2021.07.006 · Cited by 7
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“Importantly, the degree of nucleosome targeting in vivo corresponded to the factors' relative ability to bind nucleosomes in vitro.(Soufi et al., 2015) This ability to activate repressed chromatin appears to be conserved across species, as the pioneer functions of OCT4, KLF4 and SOX2 have also been observed during MEF…”
BackgroundSeATAC: a tool for exploring the chromatin landscape and the role of pioneer factors
Dsouza, N., Dsouza, N., & Garry, D. J. (2023) · Genome biology · doi:10.1186/s13059-023-02954-5 · Cited by 6
“Previous studies showed that pioneer factors such as Etv2, Ascl1, and OSK could recognize their target DNA sequences in compacted chromatin, recruit chromatin remodelers, and trigger the relaxation of the adjacent chromatin landscape to accommodate non-pioneer transcription factors [111, 112].”
BackgroundSawant, L., Thunuguntla, P., & Jones, C. (2020) · Virology · doi:10.1016/j.virol.2020.08.015 · Cited by 6
Cell Fate Programming by Transcription Factors and Epigenetic Machinery in Stomatal DevelopmentPreprint
Liu, A., Mair, A., Matos, J. L., Vollbrecht, M., Xu, S., & Bergmann, D. C. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.23.554515 · Cited by 7
Lian, T., Guan, R., Zhou, B., & Bai, Y. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.06.559923 · Cited by 7
Proliferation history and transcription factor levels drive direct conversionPreprint
Wang, N., Lende-Dorn, B. A., Adewumi, H. O., Beitz, A. M., Han, P., O’Shea, T. M., & Galloway, K. E. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.11.26.568736 · Cited by 7
“…new cell fates (Chen et al., 2021; Feng et al., 2008; Ieda et al., 2010; Lujan et al., 2012; Mall et al., 2017; Rosa et al., 2018; Son et al., 2011; Soufi et al., 2015, 2012; Sridharan et al., 2009; Takahashi and Yamanaka, 2006; Velychko et al., 2019; Wang Li et al., 2015; Wernig et al., 2008).”
Next-generation direct reprogramming
Keshri, R., Detraux, D., Phal, A., McCurdy, C., Jhajharia, S., Chan, T. C., Mathieu, J., & Ruohola‐Baker, H. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1343106 · Cited by 7
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“This notion contradicts the predictions of a previous general model proposed by Soufi et al. ( 108 ), which states that pioneer factors are able to co-bind DNA with nucleosomes efficiently through the use of partially unfolded or short alpha helices, requiring short or degenerate DNA motifs.”
Enhanced Activities of OCT4 and SOX2 Promote Epigenetic Reprogramming by Shortening G1 Phase
Guo, L., Lin, J., Ren, Q., Sun, H., Wu, Y., Ge, H., Wu, X., Lin, L., Liang, L., Li, C., et al. (2025) · Advanced Science · doi:10.1002/advs.202415528 · Cited by 6
Basis for lineage-determining pioneer factors targeting distinct repressed chromatin states
Katznelson, A., Zhang, J., Donahue, G., & Zaret, K. S. (2026) · Science Advances · doi:10.1126/sciadv.adz7409 · Cited by 7
“The closed chromatin targeting ability of pioneer factors is conferred by recognition of DNA motifs, or partial motifs, on the nucleosome surface ( 5 – 8 ).”
Self-citationReversing aging for heart repair
Wang, Y. X., & Blau, H. M. (2021) · Science · doi:10.1126/science.abl8679 · Cited by 6
Dynamic nucleosome landscape elicits a noncanonical GATA2 pioneer model
Li, T., Liu, Q., Chen, Z., Fang, K., Huang, F., Fu, X., Wang, Q., & Jin, V. X. (2022) · Nature Communications · doi:10.1038/s41467-022-30960-x · Cited by 6
“S4 was defined as Crowding array because of its higher number of 5–20 positioned nucleosomes in an array with the highest average spacing of 210.64 bp and 75.4% of states enriched with H3K9me3 and/or H3K27me3 marks.”
InfluentialInterplay between pioneer transcription factors and epigenetic modifiers in cell reprogramming
Mirizio, G. G., Sampson, S., & Iwafuchi, M. (2024) · Regenerative Therapy · doi:10.1016/j.reth.2024.12.014 · Cited by 6
“In the context of iPSC generation, three of the Yamanaka factors, OCT4, SOX2, and KLF4, are classi fi ed as pioneer TFs [3,4].”
Pioneer factors outline chromatin architecture
Gómora‐García, J. C., & Furlan-Magaril, M. (2025) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2025.102480 · Cited by 7
Rhabdomyosarcoma fusion oncoprotein initially pioneers a neural signature in vivo
Kucinski, J. P., Tallan, A. M., Taslim, C., Vontell, A. M., Silvius, K. M., Wang, M., Cannon, M. V., Stanton, B. Z., & Kendall, G. C. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115923 · Cited by 10
Defining transcription factor nucleosome binding with Pioneer-seq
Tsompana, M., Wilson, P. D., Murugaiyan, V., Handelmann, C. R., & Buck, M. J. (2025) · PLoS Genetics · doi:10.1371/journal.pgen.1011813 · Cited by 6
“The ways by which TFs recognize their TFBSs (e.g., partial motif recognition) also likely influence their ability to bind nucleosomal DNA [14].”
InfluentialYu, B., Wu, Y., & Zhao, L. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.11.181 · Cited by 6
RetractedDeciphering cis-regulatory grammar with deep learning
Miraldi, E. R., Chen, X., & Weirauch, M. T. (2021) · Nature Genetics · doi:10.1038/s41588-021-00814-1 · Cited by 6
Single-Cell Sequencing Reveals the Novel Role of Ezh2 in NK Cell Maturation and Function
Yu, M., Su, Z., Huang, X., & Wang, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.724276 · Cited by 7
“The AP-1 family is a pioneer transcription factor (TF) family with an important role in establishing new cell fate competence by granting long-term chromatin access to nonpioneer factors and is also a crucial determinant of cell identity through opening and licensing of the enhancer landscape (41, 42).”
BackgroundPre-existing chromatin accessibility of switchable repressive compartment delineates cell plasticity
Ma, X., Cao, X. D., Zhu, L., Li, Y., Wang, X., Wu, B., Wei, G., & Hui, L. (2021) · National Science Review · doi:10.1093/nsr/nwab230 · Cited by 8
“Remarkable binding of Oct4, the key factor for pluripotency induction [51], was identified in these B-to-A CSRs as well (Fig.”
Zibetti, C. (2022) · Cells · doi:10.3390/cells11050806 · Cited by 6
Shi, D., Huang, Y., & Chen, B. (2023) · Polymers · doi:10.3390/polym15071763 · Cited by 8
Examining the NEUROG2 lineage and associated gene expression in human cortical organoids
Vasan, L., Chinchalongporn, V., Saleh, F., Zinyk, D. L., Ke, C., Suresh, H., Ghazale, H., Belfiore, L., Touahri, Y., Oproescu, A.-M., et al. (2024) · Development · doi:10.1242/dev.202703 · Cited by 8
Transcriptional Regulation of the First Cell Fate Decision.
Rhee, C., Kim, J., & Tucker, H. O. (2017) · PubMed · Cited by 6
Function and regulation of transcription factors during mitosis-to-G1 transition
Soares, M. A. F., Oliveira, R. A., & Castro, D. S. (2022) · Open Biology · doi:10.1098/rsob.220062 · Cited by 7
The role of FOXA subfamily factors in embryonic development and carcinogenesis of the pancreas
Zinovyeva, M. V., Kuzmich, A. I., MONASTYRSKAYA, G. S., & Sverdlov, E. D. (2016) · Molecular Genetics Microbiology and Virology · doi:10.3103/s0891416816030113 · Cited by 6
Martin, P. C. N., & Zabet, N. R. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.11.006 · Cited by 6
“More specifically, pioneer TFs can bind sites in closed dense chromatin and subsequently open the chromatin [16, 17, 18, 19].”
BackgroundAP-1 Imprints a Reversible Transcriptional Program of Senescent CellsPreprint
Martínez-Zamudio, R. I., Roux, P., de Freitas, J. A. N. L. F., Robinson, L. J., Doré, G. R. G., Sun, B., Gil, J., Herbig, U., & Bischof, O. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/633594 · Cited by 6
The role of maternal pioneer factors in predefining first zygotic responses to inductive signalsPreprint
Gentsch, G. E., Spruce, T., Owens, N. D. L., & Smith, J. C. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/306803 · Cited by 5
DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2Preprint
Bjarnason, S., McIvor, J. A. P., Prestel, A., Demény, K. S., Bullerjahn, J. T., Kragelund, B. B., Mercadante, D., & Heidarsson, P. O. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.16.545083 · Cited by 7
Sakong, S., Fierz, B., & Suter, D. M. (2026) · Nature Communications · doi:10.1038/s41467-026-69284-5 · Cited by 9
“4d), consistent with published values 41 .”
Structural insights into the recognition of native nucleosomes by pioneer transcription factors
Zhou, B., Orris, B., Guan, R., Lian, T., & Bai, Y. (2025) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2025.103024 · Cited by 5
Exploring the Central Dogma Through the Lens of Gene Expression Noise
Verhagen, P. G. A., & Hansen, M. M. K. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169202 · Cited by 6
The reprogramming factor KLF4 in normal and malignant blood cells
Lacorazza, H. D. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1584181 · Cited by 5
Epigenetic Mechanisms of Pituitary Cell Fate Specification
Drouin, J. (2016) · Research and perspectives in endocrine interactions · doi:10.1007/978-3-319-41603-8_9 · Cited by 5
“Some pioneers such as FoxA may initially bind its targets with decreased specificity to scan the genome and then bind more firmly at pioneering sites (Soufi et al. 2015), but this still does not explain why a specific subset of sites is selected.”
BackgroundOld macrophages lose their (circadian) rhythm
McRae, H. M., & Hargreaves, D. C. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.02.005 · Cited by 6
H3K4me2 distinguishes a distinct class of enhancers during the maternal-to-zygotic transition
Hurton, M. D., Miller, J. M., & Lee, M. T. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003239 · Cited by 5
“NPS, like their mammalian counterparts, act as pioneer factors capable of binding DNA regulatory sequences in the context of condensed chromatin [5,16–20], which tends to occlude binding of non pioneers [21,22].”
Birth, P., Schöne, S., Stelzl, U., & Meijsing, S. H. (2017) · PLoS ONE · doi:10.1371/journal.pone.0181219 · Cited by 5
Networks of transcription factors
Lemus, E. H., & Tovar, H. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-817819-5.00009-7 · Cited by 4
Freewoman, J. M., Snape, R., & Cui, F. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1904554 · Cited by 5
“The partial accessibility of the BS in the nucleosome still allows subunits of p53 tetramer (e.g. a dimer) to bind, which has been shown as a feature of pioneer TFs [77] that include p53 [78].”
BackgroundPluripotency factors determine gene expression repertoire at zygotic genome activation
Gao, M., Veil, M., Rosenblatt, M., Riesle, A. J., Gebhard, A., Hass, H., Buryanova, L., Yampolsky, L. Y., Grüning, B. A., Ulianov, S. V., et al. (2022) · RePEc: Research Papers in Economics · Cited by 7
bHLH factors in neurogenesis and neuronal subtype specification
Johnson, J. E. B. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-814405-3.00014-x · Cited by 5
Zinovyeva, M. V., Kuzmich, A. I., MONASTYRSKAYA, G. S., & Sverdlov, E. D. (2016) · Molecular Genetics Microbiology and Virology (Russian) · doi:10.18821/0208-0613-2016-34-3-98-103 · Cited by 5
High-Resolution Dissection of Conducive Reprogramming Trajectory to Ground State PluripotencyPreprint
Zviran, A., Mor, N., Rais, Y., Gingold, H., Peles, S., Chomsky, E., Viukov, S. V., Buenrostro, J. D., Weinberger, L., Manor, Y. S., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/184135 · Cited by 5
CLAMP and Zelda function together to promote Drosophila zygotic genome activationPreprint
Duan, J. E., Rieder, L. E., Colonnetta, M. M., Huang, A., McKenney, M., Watters, S., Deshpande, G., Jordan, W. T., Fawzi, N. L., & Larschan, E. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.15.205054 · Cited by 6
“However, only pioneer TFs (Cirillo and Zaret, 1999; Mayran and Drouin, 2018) can bind to ‘closed’ chromatin prior to ZGA because most TFs lack the ability to bind to nucleosomal DNA (Soufi et al., 2015).”
Ranking Reprogramming Factors for Directed DifferentiationPreprint
Hammelman, J., Patel, T., Closser, M., Wichterle, H., & Gifford, D. K. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.14.444080 · Cited by 5
“…were the only two methods that highly ranked the Oct4/Sox2 heterodimer motif, which is notable as a well-known transcription factor pair in both reprogramming (Yamamizu et al. 2013; Takahashi and Yamanaka 2006) and in manipulating nucleosomes to increase chromatin accessibility (Soufi et al. 2015).”
MethodSOX transcription factors direct TCF-independent WNT/beta-catenin transcriptionPreprint
Mukherjee, S., Luedeke, D. M., Brown, L., & Zorn, A. M. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.25.457694 · Cited by 5
Yang, D., Guo, X., & Xi, R. (2025) · BioEssays · doi:10.1002/bies.70005 · Cited by 4
“For example, during OSKM-induced reprogramming, Oct4 , Sox2 , and Klf4 collaborate to activate distal enhancers critical for pluripotency, while c-Myc primarily amplifies transcriptional activity ratherthaninitiatingchromatinopening[82,83].”
Takamori, S., Haratake, N., Bhattacharya, A., Kikutake, C., Ozawa, H., Shigeta, K., Nakashoji, A., Isozaki, H., Shimokawa, M., Suyama, M., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02482-7 · Cited by 4
Freund, M. M., deHaro-Arbona, F. J., Baloul, S., Torhorst, A., Roussos, C. S., Ruffridge, A. J., Rashoff, A. Q., Hazzard, R., Lewis, P. W., Bray, S. J., et al. (2026) · Science Advances · doi:10.1126/sciadv.aef2244 · Cited by 6
Oses, C., Francia, M. G., Verneri, P., Echegaray, C. V., Guberman, A., & Levi, V. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1125015 · Cited by 6
“In this line, OCT4 and SOX2 were identified as pioneer TFs and this activity seem to be fundamental for reprogramming and differentiation (Iwafuchi-Doi and Zaret, 2014; Jerabek et al., 2014; Soufi et al., 2015; King and Klose, 2017; Roberts et al., 2021).”
BackgroundPark, C. S., Bridges, C. S., Lewis, A. H., Chen, T. J., Shai, S., Du, W., Puppi, M., Zorman, B., Pavel, S., & Lacorazza, H. D. (2025) · Experimental Hematology · doi:10.1016/j.exphem.2025.104730 · Cited by 5
Direct Reprogramming in Bone and Joint Degenerative Diseases: Applications, Obstacles and Directions
Shi, K., Li, F., Tao, Y., & Chen, Q. (2022) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x17666220810142943 · Cited by 3
The influence of high-order chromatin state in the regulation of stem cell fate
Chen, X., Lin, H., & Li, G. (2022) · Biochemical Society Transactions · doi:10.1042/bst20220763 · Cited by 4
Lin, H., Pan, Y., & Cai, S. (2023) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szad019 · Cited by 5
Transcriptional Factors Mediated Reprogramming to Pluripotency
Fatima, N., Rahman, M. S. U., Qasim, M., Ashfaq, U. A., Ahmed, U., & Masoud, M. S. (2023) · Current Stem Cell Research & Therapy · doi:10.2174/1574888x18666230417084518 · Cited by 5
Role of Nucleosome Sliding in the Protein Target Search for Covered DNA Sites
Mondal, A. K., & Kolomeisky, A. B. (2023) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.3c01704 · Cited by 4
Transcriptional and epigenetic insights from stem cells and developing tissues
Lim, D. A. (2015) · Development · doi:10.1242/dev.122424 · Cited by 4
“Thus, contrary to the popular belief that nucleosomes are inherently repressive to transcription factor binding, Zaret showed that the structural changes induced to the DNA by being wrapped around the core histones result in the presentation of partial DNA motifs to which pioneer factors can bind by adapting their DNA…”
BackgroundHistone Modifications and Histone Variants in Pluripotency and Differentiation
Bannister, A. J., Falcão, A. M., & Castelo‐Branco, G. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803395-1.00002-2 · Cited by 4
Epigenetic Landmarks During Somatic Reprogramming
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“It is interesting that all three reprogramming factors are potential pioneer factors (44).”
BackgroundCellular Reprogramming Technology for Dissecting Cancer Epigenome in Vivo
Ito, K., & Yamada, Y. (2017) · Epigenomics · doi:10.2217/epi-2017-0018 · Cited by 4
Pioneers Invade the Nucleosomal Landscape
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Profiling Accessible Chromatin and Nucleosomes in the Mammalian Genome
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Interspecies chimeras as a platform for exogenic organ production and transplantation
Garry, D. J., & Garry, M. G. (2021) · Experimental Biology and Medicine · doi:10.1177/15353702211024948 · Cited by 4
“A very small subset of master regulators, called pioneer factors, reprogram cell fate by binding transcriptionally silent genes—those that have a closed chromatin state (nuclease resistant), which are not accessible to other transcription factors (nonpioneers) (Figure 2(c)).(28,29) By relaxing the chromatin state, the…”
BackgroundHuminiecki, Ł. (2018) · PLoS ONE · doi:10.1371/journal.pone.0198961 · Cited by 4
Chromatin—a global buffer for eukaryotic gene control
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Endogenous retroviral ERVH48-1 promotes human urine cell reprogramming
Peng, Y., Zhu, J., Zhang, Q., Zhang, R., Wang, Z., Ye, Z., Ma, N., Qin, D., Pei, D., & Li, D. (2024) · Cell Regeneration · doi:10.1186/s13619-024-00200-2 · Cited by 3
“3a and b). qPCR assay showed that the expression of pluripotency genes, including SOX2, OCT4, NANOG, LIN28A, SALL4, were similar to those in H1 across all four UiPSC lines (Fig.”
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“A series of transcription factors (TFs) important for reprogramming and pluripotency, such as OCT4-SOX2-TCF-NANOG, POU5F1, SOX2, KLF1 and KLF3 [47–49] were enriched in NEU EpiSCs-only peaks (Fig.”
Cell-type-specific functionality encoded within the intrinsically disordered regions of OCT4
Ozkan, B., de Anda, M. R., Hall-Ponselé, E., Migueles, M. R. P., Alshaikh, A., Hanzevacki, M., Naama, M., Furlong, K., Roberts, G. A., Beniazza, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63806-3 · Cited by 3
“We have previously shown that OCT4 interaction with nucleosomes is essential for reprogramming 43,44,63 .”
Self-citationHuman Blastoid: A Next-Generation Model for Reproductive Medicine?
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“Unlike conventional transcription factors, PTFs interact with nucleosome-bound DNA, thus unlocking previously inaccessible DNA sequences and make them transcriptionally active (Cirillo et al., 2002; Soufi et al., 2015).”
LIN28-mediated gene regulatory loops synchronize transitions throughout organogenesis
Thevarajan, I., Osuna, M. F., Lewey, S. F., Sauceda, E., Briseno, S., Griffin, C., Kim, B. R., Rowe, R. G., da Rocha, E. L., & Osborne, J. K. (2025) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2025.102226 · Cited by 3
“Interestingly, transcriptional regulation of LIN28 has been investigated during induced pluripotent stem cell (iPSC) reprogramming by the Yamanaka factors comprised of OCT4, KLF4, SOX2 and c-MYC (OSKM) [14,15], neurogenesis via SOX2 [16], and breast cancer stem cell maintenance by B-CATENIN [17].”
PARP1 and Sox2: An Unlikely Team of Pioneers to Conquer the Nucleosome
Gaullier, G., & Luger, K. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.02.001 · Cited by 3
“In addition to the recognition of partial DNA motifs (a feature already demonstrated for Sox2; Soufi et al., 2015), PARP1-assisted chromatin binding could be a general mechanism for transcription factors for two reasons: PARP1 is bound to chromatin genome wide (Krishnakumar et al., 2008), and many…”
BackgroundFoxa2 and Pet1 Direct and Indirect Synergy Drive Serotonergic Neuronal Differentiation
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“In the 10 years since their result, many labs have tried to determine the route by which this transition can take place (Buganim et al., 2012; Soufi et al., 2012, 2015).”
Role of RUNX3 in Restriction Point Regulation
Lee, J.-W., Lee, Y., Kim, M., Chi, X., Kim, D., & Bae, S. (2023) · Cells · doi:10.3390/cells12050708 · Cited by 3
Amending the injured heart by in vivo reprogramming
Yuan, X., & Braun, T. W. (2023) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2023.102098 · Cited by 3
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ChIP-seq meta-analysis yields high quality training sets for enhancer classificationPreprint
Imrichová, H., & Aerts, S. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/388934 · Cited by 3
“The finding based on nucleosome occupancy corresponds to previously published studies where SOX2 and GRHL2 are reported as pioneer factors (Jacobs et al., 2018; Soufi et al., 2015).”
BackgroundResultInfluentialPluripotency factors determine gene expression repertoire at zygotic genome activationPreprint
Gao, M., Veil, M., Rosenblatt, M., Riesle, A. J., Gebhard, A., Hass, H., Buryanova, L., Yampolsky, L. Y., Grüning, B., Ulianov, S. V., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.16.949362 · Cited by 3
Zhou, X., Zheng, H., Fu, H., McKillip, K. D., Pinney, S. M., & Liu, Y. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.16.201350 · Cited by 3
Brown, A. K., Maybury‐Lewis, S. Y., & Webb, A. E. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.06.438676 · Cited by 3
Nucleosome topology and DNA sequence modulate the engagement of pioneer factors SOX2 and OCT4Preprint
Gadea, F. C. M., & Nikolova, E. N. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.18.476780 · Cited by 3
BRG1 generates subnucleosomes that expand OCT4 binding and function beyond DNA motifs at enhancersPreprint
Nocente, M. C., Karamitsos, A. M., Drouineau, E., Albawardi, W., Dulary, C., Ribiérre, F., Picaud, H., Alibert, O., Acker, J., Aude, J.-C., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.15.507958 · Cited by 3
Pervasive and programmed nucleosome distortion patterns on single mammalian chromatin fibersPreprint
Yang, M. G., Richter, H. J., Wang, S., McNally, C. P., Harris, N., Dhillon, S., Maresca, M., de Wit, E., Willenbring, H., Maher, J. J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.17.633622 · Cited by 3
“Genomic, structural, and other biochemical assays have offered conflicting results on how SOX2 engages chromatin, particularly regarding SOX2 interactions within the nucleosome 50,51 , versus at the nucleosome entry / exit site 49,52 .”
Burger, L., Gil, N., & Schübeler, D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.11.669605 · Cited by 3
Widespread low-affinity motifs enhance chromatin accessibility and regulatory potential in mESCsPreprint
Weilert, M., Brennan, K., Dalal, K., Krueger, S., Jiang, H., Martinez-Corral, R., & Zeitlinger, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.18.685822 · Cited by 3
“22,67 In summary, the vast majority of mapped motifs, including those with lower PWM scores, showed independent experimental evidence for being functional.”
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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