Reorganization of enhancer patterns in transition from naive to primed pluripotency
Open accessAbstract
Naive and primed pluripotency is characterized by distinct signaling requirements, transcriptomes, and developmental properties, but both cellular states share key transcriptional regulators: Oct4, Sox2, and Nanog. Here, we demonstrate that transition between these two pluripotent states is associated with widespread Oct4 relocalization, mirrored by global rearrangement of enhancer chromatin landscapes. Our genomic and biochemical analyses identified candidate mediators of primed state-specific Oct4 binding, including Otx2 and Zic2/3. Even when differentiation cues are blocked, premature Otx2 overexpression is sufficient to exit the naive state, induce transcription of a substantial subset of primed pluripotency-associated genes, and redirect Oct4 to previously inaccessible enhancer sites. However, the ability of Otx2 to engage new enhancer regions is determined by its levels, cis-encoded properties of the sites, and the signaling environment. Our results illuminate regulatory mechanisms underlying pluripotency and suggest that the capacity of transcription factors such as Otx2 and Oct4 to pioneer new enhancer sites is highly context dependent.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The pluripotency-associated pioneer factor OCT4 dramatically switches enhancers upon transition from an embryonic stem cell to an epiblast-like cell state.
“For example, the pluripotency-associated pioneer factor OCT4 dramatically switches enhancers upon transition from an embryonic stem cell to an epiblast-like cell state (Buecker et al., 2014).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Buecker et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A unique chromatin signature uncovers early developmental enhancers in humans
Rada-Iglesias, A., Bajpai, R., Swigut, T., Brugmann, S. A., Flynn, R. A., & Wysocka, J. (2011) · Nature · doi:10.1038/nature09692 · Cited by 2,233 · see citing works
Self-citationMediator and cohesin connect gene expression and chromatin architecture
Kagey, M. H., Newman, J. J., Bilodeau, S., Zhan, Y., Orlando, D. A., van Berkum, N. L., Ebmeier, C. C., Goossens, J., Rahl, P. B., Levine, S. S., et al. (2010) · Nature · doi:10.1038/nature09380 · Cited by 1,939 · see citing works
An Oct4-Centered Protein Interaction Network in Embryonic Stem Cells
van den Berg, D. L. C., Snoek, T., Mullin, N. P., Yates, A., Bezstarosti, K., Demmers, J., Chambers, I., & Poot, R. A. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.02.014 · Cited by 542 · see citing works
Oct4 links multiple epigenetic pathways to the pluripotency network
Ding, J., Xu, H., Faiola, F., Ma'ayan, A., & Wang, J. (2012) · Cell Research · doi:10.1038/cr.2011.179 · Cited by 162 · see citing works
Flagged first, then by citations
Research works printed but not linked: 39
- Acampora D Di Giovannantonio LG Simeone A Otx2 is an intrinsic determinant of the embryonic stem cell state and is required for transition to a stable epiblast stem cell condition Dev. Camb. Engl 2013 140 43 55 23154415
- Bailey TL Boden M Buske FA Frith M Grant CE Clementi L Ren J Li WW Noble WS MEME Suite: tools for motif discovery and searching Nucleic Acids Res 2009 37 W202 W208 19458158 PMC2703892
- Betschinger J Nichols J Dietmann S Corrin PD Paddison PJ Smith A Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3 Cell 2013 153 335 347 23582324 PMC3661979
- Boiani M Schöler HR Regulatory networks in embryo-derived pluripotent stem cells Nat. Rev. Mol. Cell Biol 2005 6 872 884 16227977
- Bonn S Zinzen RP Girardot C Gustafson EH Perez-Gonzalez A Delhomme N Ghavi-Helm Y Wilczyński B Riddell A Furlong EEM Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development Nat. Genet 2012 22231485
- Calo E Wysocka J Modification of enhancer chromatin: what, how, and why? Mol. Cell 2013 49 825 837 23473601 PMC3857148
- Chan Y-S Göke J Ng J-H Lu X Gonzales KAU Tan C-P Tng W-Q Hong Z-Z Lim Y-S Ng H-H Induction of a Human Pluripotent State with Distinct Regulatory Circuitry that Resembles Preimplantation Epiblast Cell Stem Cell 2013 13 663 675 24315441
- Chen X Xu H Yuan P Fang F Huss M Vega VB Wong E Orlov YL Zhang W Jiang J Integration of external signaling pathways with the core transcriptional network in embryonic stem cells Cell 2008 133 1106 1117 18555785
- Cirillo LA Lin FR Cuesta I Friedman D Jarnik M Zaret KS Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4 Mol. Cell 2002 9 279 289 11864602
- Consortium TEP An integrated encyclopedia of DNA elements in the human genome Nature 2012 489 57 74 22955616 PMC3439153
- Creyghton MP Cheng AW Welstead GG Kooistra T Carey BW Steine EJ Hanna J Lodato MA Frampton GM Sharp PA Histone H3K27ac separates active from poised enhancers and predicts developmental state Proc. Natl. Acad. Sci. U. S. A 2010 107 21931 21936 21106759 PMC3003124
- ENCODE Project Consortium A user’s guide to the encyclopedia of DNA elements (ENCODE) PLoS Biol 2011 9 e1001046 21526222 PMC3079585
- Gafni O Weinberger L Mansour AA Manor YS Chomsky E Ben-Yosef D Kalma Y Viukov S Maza I Zviran A Derivation of novel human ground state naive pluripotent stem cells Nature 2013 24172903
- Gibcus JH Dekker J The hierarchy of the 3D genome Mol. Cell 2013 49 773 782 23473598 PMC3741673
- Grant CE Bailey TL Noble WS FIMO: scanning for occurrences of a given motif Bioinformatics 2011 27 1017 1018 21330290 PMC3065696
- Guo G Yang J Nichols J Hall JS Eyres I Mansfield W Smith A Klf4 reverts developmentally programmed restriction of ground state pluripotency Development 2009 136 1063 1069 19224983 PMC2685927
- Hayashi K Ohta H Kurimoto K Aramaki S Saitou M Reconstitution of the Mouse Germ Cell Specification Pathway in Culture by Pluripotent Stem Cells Cell 2011 21820164
- Heinz S Romanoski CE Benner C Allison KA Kaikkonen MU Orozco LD Glass CK Effect of natural genetic variation on enhancer selection and function Nature 2013 503 487 492 24121437 PMC3994126
- Herr W Cleary MA The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain Genes Dev 1995 9 1679 1693 7622033
- Jolma A Yan J Whitington T Toivonen J Nitta KR Rastas P Morgunova E Enge M Taipale M Wei G DNA-binding specificities of human transcription factors Cell 2013 152 327 339 23332764
- Karwacki-Neisius V Göke J Osorno R Halbritter F Ng JH Weiβe AY Wong FCK Gagliardi A Mullin NP Festuccia N Reduced Oct4 expression directs a robust pluripotent state with distinct signaling activity and increased enhancer occupancy by Oct4 and Nanog Cell Stem Cell 2013 12 531 545 23642364 PMC3650585
- Kojima Y Kaufman-Francis K Studdert JB Steiner KA Power MD Loebel DAF Jones V Hor A de Alencastro G Logan GJ The Transcriptional and Functional Properties of Mouse Epiblast Stem Cells Resemble the Anterior Primitive Streak Cell Stem Cell 2013 24139757
- Kunath T Saba-El-Leil MK Almousailleakh M Wray J Meloche S Smith A FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment Dev. Camb. Engl 2007 134 2895 2902 17660198
- Miller JA Widom J Collaborative competition mechanism for gene activation in vivo Mol. Cell. Biol 2003 23 1623 1632 12588982 PMC151720
- Mirny LA Nucleosome-mediated cooperativity between transcription factors Proc. Natl. Acad. Sci. U. S. A 2010 107 22534 22539 21149679 PMC3012490
- Moyle-Heyrman G Tims HS Widom J Structural constraints in collaborative competition of transcription factors against the nucleosome J. Mol. Biol 2011 412 634 646 21821044 PMC3534743
- Mullen AC Orlando DA Newman JJ Lovén J Kumar RM Bilodeau S Reddy J Guenther MG Dekoter RP Young RA Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling Cell 2011 147 565 576 22036565 PMC3212730
- Nakaki F Hayashi K Ohta H Kurimoto K Yabuta Y Saitou M Induction of mouse germ-cell fate by transcription factors in vitro Nature 2013 23913270
- Nichols J Smith A Naive and primed pluripotent states Cell Stem Cell 2009 4 487 492 19497275
- Pardo M Lang B Yu L Prosser H Bradley A Babu MM Choudhary J An expanded Oct4 interaction network: implications for stem cell biology, development, and disease Cell Stem Cell 2010 6 382 395 20362542 PMC2860244
- Pesce M Schöler HR Oct-4: gatekeeper in the beginnings of mammalian development Stem Cells Dayt. Ohio 2001 19 271 278 11463946
- Radzisheuskaya A Chia GLB dos Santos RL Theunissen TW Castro LFC Nichols J Silva JCR A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages Nat. Cell Biol 2013 15 579 590 23629142 PMC3671976
- Rais Y Zviran A Geula S Gafni O Chomsky E Viukov S Mansour AA Caspi I Krupalnik V Zerbib M Deterministic direct reprogramming of somatic cells to pluripotency Nature 2013 502 65 70 24048479
- Soufi A Donahue G Zaret KS Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome Cell 2012 151 994 1004 23159369 PMC3508134
- Spitz F Furlong EEM Transcription factors: from enhancer binding to developmental control Nat. Rev. Genet 2012 13 613 626 22868264
- Tesar PJ Chenoweth JG Brook FA Davies TJ Evans EP Mack DL Gardner RL McKay RDG New cell lines from mouse epiblast share defining features with human embryonic stem cells Nature 2007 448 196 199 17597760
- Trompouki E Bowman TV Lawton LN Fan ZP Wu D-C Dibiase A Martin CS Cech JN Sessa AK Leblanc JL Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs during Differentiation and Regeneration Cell 2011 147 577 589 22036566 PMC3219441
- Yáñez-Cuna JO Dinh HQ Kvon EZ Shlyueva D Stark A Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding Genome Res 2012 22 2018 2030 22534400 PMC3460196
- Zinzen RP Girardot C Gagneur J Braun M Furlong EEM Combinatorial binding predicts spatio-temporal cis-regulatory activity Nature 2009 462 65 70 19890324
Cited by
Sorted by citations
Functional annotation of native enhancers with a Cas9–histone demethylase fusion
Kearns, N. A., Pham, H., Tabak, B., Genga, R. M., Silverstein, N. J., Garber, M., & Maehr, R. (2015) · Nature Methods · doi:10.1038/nmeth.3325 · Cited by 656 · see citing works
Base-resolution models of transcription-factor binding reveal soft motif syntax
Avsec, Ž., Weilert, M., Shrikumar, A., Krueger, S., Alexandari, A., Dalal, K., Fropf, R., McAnany, C., Gagneur, J., Kundaje, A., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00782-6 · Cited by 610 · see citing works
Dynamic stem cell states: Naive to primed pluripotency in rodents and humans
Weinberger, L., Ayyash, M., Novershtern, N., & Hanna, J. H. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2015.28 · Cited by 622 · see citing works
Dorighi, K. M., Swigut, T., Henriques, T., Bhanu, N. V., Scruggs, B. S., Nady, N., Still, C. D., Garcia, B. A., Adelman, K., & Wysocka, J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.018 · Cited by 403 · see citing works
Self-citationCruz-Molina, S., Respuela, P., Tebartz, C., Kolovos, P., Nikolic, M., Fueyo, R., van Ijcken, W. F. J., Grosveld, F., Frommolt, P., Bazzi, H., et al. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.02.004 · Cited by 240 · see citing works
Kang, K., Park, S. H., Chen, J., Qiao, Y., Giannopoulou, E., Berg, K., Hanidu, A., Li, J., Nabozny, G., Kang, K., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.07.017 · Cited by 196 · see citing works
Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex
Shen, H., Xu, W., Guo, R., Rong, B., Gu, L., Wang, Z., He, C., Zheng, L., Hu, X., Hu, Z., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.064 · Cited by 184 · see citing works
NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers
Murakami, K., Günesdogan, U., Zylicz, J. J., Tang, W. W. C., Sengupta, R., Kobayashi, T., Kim, S., Butler, R., Dietmann, S., & Azim Surani, M. (2016) · Nature · doi:10.1038/nature16480 · Cited by 180 · see citing works
Messmer, T., von Meyenn, F., Savino, A., Santos, F., Mohammed, H., Lun, A. T. L., Marioni, J. C., & Reik, W. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.099 · Cited by 156 · see citing works
Multi-omic Profiling Reveals Dynamics of the Phased Progression of Pluripotency
Yang, P., Humphrey, S. J., Cinghu, S., Pathania, R., Oldfield, A. J., Kumar, D., Perera, D., Yang, J. Y. H., James, D. E., Mann, M., et al. (2019) · Cell Systems · doi:10.1016/j.cels.2019.03.012 · Cited by 146 · see citing works
Profiling chromatin states using single-cell itChIP-seq
Ai, S., Xiong, H., Li, C. C., Luo, Y., Shi, Q., Liu, Y., Yu, X., Li, C., & He, A. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0383-5 · Cited by 140 · see citing works
Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation
Alder, O., Cullum, R., Lee, S., Kan, A. C., Wei, W., Yi, Y., Garside, V. C., Bilenky, M., Griffith, M., Morrissy, A. S., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.08.046 · Cited by 113 · see citing works
“For example, the pluripotency-associated pioneer factor OCT4 dramatically switches enhancers upon transition from an embryonic stem cell to an epiblast-like cell state (Buecker et al., 2014).”
BackgroundLysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3
Villegas, F., Lehalle, D., Mayer, D., Rittirsch, M., Stadler, M. B., Zinner, M., Olivieri, D., Vabres, P., Duplomb-Jego, L., De Bont, E. S. J. M., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.11.021 · Cited by 110 · see citing works
scMAGeCK links genotypes with multiple phenotypes in single-cell CRISPR screens
Yang, L., Zhu, Y., Yu, H., Cheng, X., Chen, S., Chu, Y., Huang, H., Zhang, J., & Li, W. (2020) · Genome Biology · doi:10.1186/s13059-020-1928-4 · Cited by 94 · see citing works
ATF3 drives senescence by reconstructing accessible chromatin profiles
Zhang, C., Zhang, X., Huang, L., Guan, Y., Huang, X., Tian, X., Zhang, L., & Tao, W. (2021) · Aging Cell · doi:10.1111/acel.13315 · Cited by 84 · see citing works
“It is worth noting that there distributes strong enhancer in the IARs near FGF5 (Buecker et al., 2014).”
BackgroundLong-range regulation of transcription scales with genomic distance in a gene-specific manner
Jensen, C. L., Chen, L.-F., Swigut, T., Crocker, O. J., Yao, D., Bassik, M. C., Ferrell, J. E., Boettiger, A. N., & Wysocka, J. (2025) · Molecular Cell · doi:10.1016/j.molcel.2024.10.021 · Cited by 39 · see citing works
Self-citationWhat Can Stem Cell Models Tell Us About Human Germ Cell Biology?
Irie, N., Sybirna, A., & Surani, M. A. (2018) · Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2018.02.010 · Cited by 22 · see citing works
Sadalge, D., Clasman, J. R., Topal, S., Musser, D., Von der Porten, L., Wu, S., Schultz, S. E., Austin, W., Huang, D., Gao, Y.-D., et al. (2025) · doi:10.1101/2025.08.01.667454 · Cited by 2 · see citing works
- Authors
- Buecker, C., Srinivasan, R., Wu, Z., Calo, E., Acampora, D., Faial, T., Simeone, A., Tan, M., Swigut, T., & Wysocka, J.
- Affiliations
- Stanford Medicine (US)
- Chinese Academy of Sciences (CN)
- Istituto Neurologico Mediterraneo (IT)
- Corresponding author
- Wysocka, Joanna
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 14
- Issue
- 6
- Pages
- 838-853
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC4491504
- OpenAlex
- W2044830131
- Cited by
- 507
- References
- 4
- Citations by year
- 2026: 24 · 2025: 42 · 2024: 34 · 2023: 44 · 2022: 41 · 2021: 54 · 2020: 36 · 2019: 36 · 2018: 57 · 2017: 52 · 2016: 37 · 2015: 35 · 2014: 12 · 2013: 1
- FWCI
- 18.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Human Genome Research Institute (5 T32 HG 44-17)
- National Institute of General Medical Sciences (P01GM099130)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- naive pluripotency, primed pluripotency, naïve-to-primed transition, Otx2, ZIC2, ZIC3, transcription factor binding, pioneer transcription factors
- MeSH terms
- Animals, Cells, Cultured, Enhancer Elements, Genetic, Pluripotent Stem Cells, Octamer Transcription Factor-3, Mice, Otx Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
