PRC2 Facilitates the Regulatory Topology Required for Poised Enhancer Function during Pluripotent Stem Cell Differentiation
Open accessAbstract
Poised enhancers marked by H3K27me3 in pluripotent stem cells have been implicated in the establishment of somatic expression programs during embryonic stem cell (ESC) differentiation. However, the functional relevance and mechanism of action of poised enhancers remain unknown. Using CRISPR/Cas9 technology to engineer precise genetic deletions, we demonstrate that poised enhancers are necessary for the induction of major anterior neural regulators. Interestingly, circularized chromosome conformation capture sequencing (4C-seq) shows that poised enhancers already establish physical interactions with their target genes in ESCs in a polycomb repressive complex 2 (PRC2)-dependent manner. Loss of PRC2 does not activate poised enhancers or induce their putative target genes in undifferentiated ESCs; however, loss of PRC2 in differentiating ESCs severely and specifically compromises the induction of major anterior neural genes representing poised enhancer targets. Overall, our work illuminates an unexpected function for polycomb proteins in facilitating neural induction by endowing major anterior neural loci with a permissive regulatory topology.
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Many developmental enhancers are found in the poised or Polycomb-repressed state in early development.
“Many developmental enhancers are found in the poised or Polycomb-repressed state in early development [139, 142, 143], and the functional role of these states remains an area of active research.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [143]
Some contacts between PcG-associated regions, including poised promoters and enhancers in ESCs, are retained after these regions are activated during cell differentiation.
“Notably, some contacts between PcG-associated regions, including poised promoters and enhancers in ESCs, are retained after these regions are activated during cell differentiation [141, 143].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [143]
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BackgroundCardozo Gizzi, A. M., Cattoni, D. I., Fiche, J.-B., Espinola, S. M., Gurgo, J., Messina, O., Houbron, C., Ogiyama, Y., Papadopoulos, G. L., Cavalli, G., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.01.011 · Cited by 258 · see citing works
Diversity and Emerging Roles of Enhancer RNA in Regulation of Gene Expression and Cell Fate
Arnold, P. R., Wells, A. D., & Li, X. C. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00377 · Cited by 247 · see citing works
“Finally, Polycomb PRC2 has also been shown to interact with Mediator, maintain looping in poised enhancers, and bind nascent RNAs (Kaneko et al., 2013; Fukasawa et al., 2015; Cruz-Molina et al., 2017).”
BackgroundGenome-wide mapping of G-quadruplex structures with CUT&Tag
Lyu, J., Shao, R., Yung, P. Y. K., & Elsässer, S. J. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1073 · Cited by 225 · see citing works
“H3K27ac, H3K4me1, H3K27me3, canonical and non-canonical PQS at active enhancer (active), primed enhancer (primed) and poised enhancer (poised) regions (61).”
InfluentialThe Bivalent Genome: Characterization, Structure, and Regulation
Blanco, E., González-Ramírez, M., Alcaine-Colet, A., Aranda, S., & Croce, L. D. (2019) · Trends in Genetics · doi:10.1016/j.tig.2019.11.004 · Cited by 215 · see citing works
Landscape of cohesin-mediated chromatin loops in the human genome
Grubert, F., Srivas, R., Spacek, D. V., Kasowski, M. M., Ruiz-Velasco, M., Sinnott-Armstrong, N., Greenside, P., Narasimha, A. M., Liu, Q., Geller, B. S., et al. (2020) · Nature · doi:10.1038/s41586-020-2151-x · Cited by 201 · see citing works
Regulatory Landscaping: How Enhancer-Promoter Communication Is Sculpted in 3D
Robson, M. I., Ringel, A. R., & Mundlos, S. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.05.032 · Cited by 188 · see citing works
Regulation, functions and transmission of bivalent chromatin during mammalian development
Macrae, T. A., Fothergill-Robinson, J., & Ramalho‐Santos, M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00518-2 · Cited by 186 · see citing works
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Independence of chromatin conformation and gene regulation during Drosophila dorsoventral patterning
Ing-Simmons, E., Vaid, R., Bing, X. Y., Levine, M., Mannervik, M., & Vaquerizas, J. M. (2021) · Nature Genetics · doi:10.1038/s41588-021-00799-x · Cited by 159 · see citing works
Promoter bivalency favors an open chromatin architecture in embryonic stem cells
Martín, G. M., Blanco, E., Ballaré, C., Sansó, M., Spill, Y. G., Hu, D., Aoi, Y., Dily, F. L., Shilatifard, A., Martı́-Renom, M. A., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0218-5 · Cited by 148 · see citing works
Chromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development
Ngan, C. Y., Wong, C. H., Tjong, H., Wang, W., Goldfeder, R. L., Choi, C., He, H., Gong, L., Lin, J., Urban, B., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0581-x · Cited by 140 · see citing works
The three-dimensional genome: regulating gene expression during pluripotency and development
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“These regions are enriched for H3K27me3 and interact with their putative target genes, prior to their activation, in a PRC2-dependent manner (Cruz-Molina et al., 2017).”
BackgroundPachano, T., Sánchez-Gaya, V., Ealo, T., Mariner-Faulí, M., Bleckwehl, T., Asenjo, H. G., Respuela, P., Cruz-Molina, S., Muñoz-San Martín, M., Haro, E., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00888-x · Cited by 116 · see citing works
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Self-citationClose to the edge: Heterochromatin at the nucleolar and nuclear peripheries
Bizhanova, A., & Kaufman, P. D. (2020) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2020.194666 · Cited by 107 · see citing works
Proximity labeling identifies a repertoire of site-specific R-loop modulators
Yan, Q., Wulfridge, P., Doherty, J. K., Fernández-Luna, J. L., Real, P. J., Tang, H., & Sarma, K. (2022) · Nature Communications · doi:10.1038/s41467-021-27722-6 · Cited by 103 · see citing works
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Self-citationLi, M., Yu, J. S. L., Tilgner, K., Ong, S., Koike-Yusa, H., & Yusa, K. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.027 · Cited by 81 · see citing works
“In the nucleus, several chromatin-modifying and chromatin-remodeling complexes were identified (Cruz-Molina et al., 2017; Kaji et al., 2006; Whyte et al., 2012).”
Chromatin Regulation of Neuronal Maturation and Plasticity
Gallegos, D. A., Chan, U., Chen, L., & West, A. E. (2018) · Trends in Neurosciences · doi:10.1016/j.tins.2018.02.009 · Cited by 93 · see citing works
Petracovici, A., & Bonasio, R. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.03.038 · Cited by 91 · see citing works
Peng, T., Zhai, Y., Atlasi, Y., ter Huurne, M., Marks, H., Stunnenberg, H. G., & Megchelenbrink, W. (2020) · Genome Biology · doi:10.1186/s13059-020-02156-3 · Cited by 83 · see citing works
“For example, “poised enhancers,” that are occupied by P300 and establish significant interactions with promoters of lineage specifying genes in ESCs, are repressed by H3K27me3 [35].”
BackgroundInfluentialForces driving the three‐dimensional folding of eukaryotic genomes
Rada-Iglesias, Á., Grosveld, F. G., & Papantonis, A. (2018) · Molecular Systems Biology · doi:10.15252/msb.20188214 · Cited by 81 · see citing works
“…encounters between genes and their cognate enhancers can be facilitated by either pre-formed contacts (Ghavi-Helm et al , 2014; Kolovos et al , 2016; Cruz-Molina et al , 2017) or increased mobility due to the activity of the polymerase and/or cohesin (Busslinger et al , 2017; Gu et al , 2018).”
Self-citationTranscriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
“Notably, some contacts between PcG-associated regions, including poised promoters and enhancers in ESCs, are retained after these regions are activated during cell differentiation [141, 143].”
BackgroundHighly enriched BEND3 prevents the premature activation of bivalent genes during differentiation
Zhang, J., Zhang, Y., You, Q., Huang, C., Zhang, T., Wang, M., Zhang, T., Yang, X., Xiong, J., Li, Y., et al. (2022) · Science · doi:10.1126/science.abm0730 · Cited by 80 · see citing works
HiCAR is a robust and sensitive method to analyze open-chromatin-associated genome organization
Wei, X., Yu, X., Peters, D., Marius, C., Sun, T., Shan, R., Ou, J., Lin, X., Yue, F., Li, W., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.01.023 · Cited by 83 · see citing works
King, D., Hong, C. K., Shepherdson, J. L., Granas, D. M., Maricque, B. B., & Cohen, B. A. (2020) · eLife · doi:10.7554/elife.41279 · Cited by 76 · see citing works
“Alternatively, accessible regions may be bound by transcription factors but may not necessarily drive activity, such as in the case of ‘poised’ regulatory elements (Cruz-Molina et al., 2017).”
BackgroundEpigenetic control of transcriptional regulation in pluripotency and early differentiation
Gökbuget, D., & Blelloch, R. H. (2019) · Development · doi:10.1242/dev.164772 · Cited by 69 · see citing works
“A recent study also discovered that some of the poised enhancers in ESCs are near genes that gain activity in anterior neural progenitors (AntNPCs), correlating with accumulation of H3K27ac at those enhancers (Cruz-Molina et al., 2017).”
BackgroundThe chromatin signatures of enhancers and their dynamic regulation
Barral, A., & Déjardin, J. (2023) · Nucleus · doi:10.1080/19491034.2022.2160551 · Cited by 71 · see citing works
“First, at the recruitment level: the Suppressor of Zeste 12 (Suz12), a PRC2 core subunit, is unable to recruit PRC2 on enhancer since it is sequestered by transcription elongation factor SPT6 [155].”
BackgroundInfluentialPolycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genesPreprint
King, H. W., Fursova, N., Blackledge, N. P., & Klose, R. J. (2018) · Genome Research · doi:10.1101/gr.237180.118 · Cited by 69 · see citing works
Cell Fate and Developmental Regulation Dynamics by Polycomb Proteins and 3D Genome Architecture
Loubière, V., Martinez, A., & Cavalli, G. (2019) · BioEssays · doi:10.1002/bies.201800222 · Cited by 64 · see citing works
Cieślak, A., Charbonnier, G., Tesio, M., Mathieu, È.-L., Belhocine, M., Touzart, A., Smith, C. L., Hypolite, G., Andrieu, G. P., Martens, J. H. A., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20192360 · Cited by 62 · see citing works
“activity, as suggested for developmentally regulated enhancers (Cruz-Molina et al., 2017; Rada-Iglesias et al., 2011; Zentner et al., 2011).”
BackgroundImplications of Enhancer Transcription and eRNAs in Cancer
Adhikary, S., Roy, S., Chacon, J. A., Gadad, S. S., & Das, C. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-4010 · Cited by 62 · see citing works
“Likewise, PRC2, which trimethylates H3K27, interacts with the mediator complex, assisting in poised enhancers’ looping by binding to RNA (77, 78).”
BackgroundEnhancer-gene specificity in development and disease
Pachano, T., Haro, E., & Rada-Iglesias, Á. (2022) · Development · doi:10.1242/dev.186536 · Cited by 55 · see citing works
Ferrai, C., Triglia, E. T., Risner-Janiczek, J. R., Rito, T., Rackham, O. J. L., de Santiago, I., Kukalev, A., Nicodemi, M., Akalin, A., Li, M., et al. (2017) · Molecular Systems Biology · doi:10.15252/msb.20177754 · Cited by 55 · see citing works
Genome-Wide Estrogen Receptor Activity in Breast Cancer
Farcas, A. M., Nagarajan, S., Cosulich, S. C., & Carroll, J. S. (2020) · Endocrinology · doi:10.1210/endocr/bqaa224 · Cited by 58 · see citing works
Chromatin Conformation in Development and Disease
Boltsis, I., Grosveld, F. G., Giraud, G., & Kolovos, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.723859 · Cited by 56 · see citing works
Self-citationTopologically Associating Domains and Regulatory Landscapes in Development, Evolution and Disease
Tena, J. J., & Santos-Pereira, J. M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.702787 · Cited by 55 · see citing works
Dissecting embryonic and extraembryonic lineage crosstalk with stem cell co-culture
Wei, Y., Zhang, E., Yu, L., Ci, B., Sakurai, M., Guo, L. M., Zhang, X., Lin, S., Takii, S., Liu, L., et al. (2023) · Cell · doi:10.1016/j.cell.2023.11.008 · Cited by 51 · see citing works
Multicenter integrated analysis of noncoding CRISPRi screens
Yao, D., Tycko, J., Oh, J. W., Bounds, L. R., Gosai, S. J., Lataniotis, L., Mackay-Smith, A., Doughty, B. R., Gabdank, I., Schmidt, H., et al. (2024) · Nature Methods · doi:10.1038/s41592-024-02216-7 · Cited by 61 · see citing works
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Regulation of Chromatin Structure During Neural Development
Kishi, Y., & Gotoh, Y. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00874 · Cited by 50 · see citing works
Enhancer-associated H3K4 methylation safeguards in vitro germline competence
Bleckwehl, T., Crispatzu, G., Schaaf, K., Respuela, P., Bartusel, M., Benson, L. J., Clark, S. J., Dorighi, K. M., Barral, A., Laugsch, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26065-6 · Cited by 53 · see citing works
Self-citationChromatin folding and nuclear architecture: PRC1 function in 3D
Illingworth, R. S. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.06.006 · Cited by 48 · see citing works
Xu, H., Zhang, S., Yi, X., Plewczyński, D., & Li, M. J. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.02.013 · Cited by 48 · see citing works
“Studies have shown that poised enhancers can physically contact their target genes by polycomb dependent manner in certain cellular and genomic contexts, but the permissive EPIs will be silent until receiving active nuclear signatures [48,49].”
BackgroundBlümli, S., Wiechens, N., Wu, M., Singh, V., Gierliński, M., Schweikert, G., Gilbert, N., Naughton, C., Sundaramoorthy, R., Varghese, J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109943 · Cited by 50 · see citing works
Epigenetic and Transcriptional Pre-patterning—An Emerging Theme in Cortical Neurogenesis
Albert, M., & Huttner, W. Β. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00359 · Cited by 50 · see citing works
“In addition, PcG proteins have been proposed to facilitate neural induction by establishing physical interactions between poised enhancers and their target genes in embryonic stem cells (Cruz-Molina et al., 2017).”
BackgroundFoxP3 associates with enhancer-promoter loops to regulate Treg-specific gene expressionPreprint
Ramírez, R. N., Chowdhary, K., Léon, J., Mathis, D. J., & Benoist, C. O. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.12.468430 · Cited by 49 · see citing works
The 3D enhancer network of the developing T cell genome is shaped by SATB1
Zelenka, T., Klonizakis, A., Tsoukatou, D., Papamatheakis, D.-A., Franzenburg, S., Tzerpos, P., Tzonevrakis, I.-R., Papadogkonas, G., Kapsetaki, M., Nikolaou, C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34345-y · Cited by 42 · see citing works
Chromatin topology in development and disease
Bompadre, O., & Andrey, G. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.04.007 · Cited by 46 · see citing works
A nuclease- and bisulfite-based strategy captures strand-specific R-loops genome-wide
Wulfridge, P., & Sarma, K. (2021) · eLife · doi:10.7554/elife.65146 · Cited by 49 · see citing works
“To determine differential R-loop formation across enhancers, we examined R-loop signal across active, poised, and primed enhancers in mESCs (Cruz-Molina et al., 2017).”
BackgroundThe nuclear periphery is a scaffold for tissue-specific enhancers
Smith, C. L., Poleshko, A., & Epstein, J. A. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab392 · Cited by 44 · see citing works
“In this study, we identified KODs in undifferentiated mESCs, so we made use of enhancer state designations of active, primed, or poised from undifferentiated mESCs (57).”
BackgroundMethodInfluentialDynamic 3D Chromatin Reorganization during Establishment and Maintenance of Pluripotency
Pelham‐Webb, B., Murphy, D., & Apostolou, E. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.10.012 · Cited by 43 · see citing works
“This suggests that developmentally relevant chromatin structures may be already established in PSCs, as shown before (Cruz-Molina et al., 2017; Rubin et al., 2017; Schoenfelder et al., 2015a), but also selectively maintained during mitosis to enable rapid G1 activation and differentiation uponproper stimulation.”
BackgroundGentile, C., Berlivet, S., Mayran, A., Paquette, D., Guerard-Millet, F., Bajon, E., Dostie, J., & Kmita, M. (2018) · Developmental Cell · doi:10.1016/j.devcel.2019.05.021 · Cited by 46 · see citing works
The multiscale effects of polycomb mechanisms on 3D chromatin folding
Cheutin, T., & Cavalli, G. (2019) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2019.1679082 · Cited by 43 · see citing works
“PRC2 is required for the establishment of contacts between poised enhancers and their target genes in ESCs (Cruz-Molina et al. 2017).”
BackgroundComoglio, F., Park, H. J., Schoenfelder, S., Barozzi, I., Bode, D., Fraser, P., & Green, A. R. (2018) · Genome Research · doi:10.1101/gr.227272.117 · Cited by 41 · see citing works
“…methods and derivatives identified two types of enhancer-promoter interactions: loops formed de novo and pre-existing loops (Melo et al. 2013; Eijkelenboom et al. 2014; Freire-Pritchett et al. 2017; Montavon et al. 2011; Ghavi-Helm et al. 2014; Apostolou et al. 2013; Cruz-Molina et al. 2017).”
BackgroundPRC2, Chromatin Regulation, and Human Disease: Insights From Molecular Structure and Function
Liu, X., & Liu, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.894585 · Cited by 44 · see citing works
“Likewise, PRC2 facilitates contact between poised enhancers and target genes during mESC differentiation (127).”
BackgroundPHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells
Jain, P., Ballaré, C., Blanco, E., Vizán, P., & Croce, L. D. (2020) · eLife · doi:10.7554/elife.51373 · Cited by 41 · see citing works
López-Anguita, N., Gassaloglu, S. I., Stötzel, M., Typou, M., Virta, I., Hetzel, S., Buschow, R., Koksal, B., Atilla, D., Maitschke-Rajasekharan, R., et al. (2022) · Development · doi:10.1242/dev.200679 · Cited by 37 · see citing works
Enhancer DNA methylation in acute myeloid leukemia and myelodysplastic syndromes
Benetatos, L., & Vartholomatos, G. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2783-2 · Cited by 40 · see citing works
An EZH2-dependent transcriptional complex promotes aberrant epithelial remodelling after injury
Le, H. Q., Hill, M. A., Kollak, I., Keck, M., Schroeder, V., Wirth, J., Skrońska-Wąsek, W., Schruf, E., Strobel, B., Stahl, H. F., et al. (2021) · EMBO Reports · doi:10.15252/embr.202152785 · Cited by 39 · see citing works
“…embryonic stem cells have suggested that the transition to non-canonical EZH2 is mediated by the occupancy of poised POL2 on target genes in a permissive chromatin environment that primes enhancer – promoter interactions for future gene activation (Brookes et al , 2012; Cruz-Molina et al , 2017).”
The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency
Festuccia, N., Owens, N. D. L., Chervova, A. A., Dubois, A., & Navarro, P. (2021) · Development · doi:10.1242/dev.199604 · Cited by 39 · see citing works
“…Esrrb and Nr5a2 relative levels of expression was obtained from supplementary tables available in the previously published studies (Atlasi et al., 2019; Buecker et al., 2014; Cruz-Molina et al., 2017; Dunn et al., 2019; Ficz et al., 2013; Gu et al., 2016a; Hsu et al., 2019; vonMeyenn et al., 2016).”
MethodWang, A. H., Juan, A. H., Ko, K. D., Tsai, P.-F., Zare, H., Dell’Orso, S., & Sartorelli, V. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.09.016 · Cited by 35 · see citing works
p300/CBP sustains Polycomb silencing by non-enzymatic functions
Hunt, G., Boija, A., & Mannervik, M. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.09.005 · Cited by 34 · see citing works
Generation and validation of versatile inducible CRISPRi embryonic stem cell and mouse model
Li, R., Xia, X., Wang, X., Sun, X., Dai, Z., Huo, D., Zheng, H., Xiong, H., He, A., & Wu, X. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000749 · Cited by 35 · see citing works
Histone H2A Monoubiquitination in Neurodevelopmental Disorders
Srivastava, A., McGrath, B., & Bielas, S. L. (2017) · Trends in Genetics · doi:10.1016/j.tig.2017.06.002 · Cited by 35 · see citing works
Distinct features of nucleolus-associated domains in mouse embryonic stem cells
Bizhanova, A., Yan, A., Yu, J., Zhu, L. J., & Kaufman, P. D. (2020) · Chromosoma · doi:10.1007/s00412-020-00734-9 · Cited by 34 · see citing works
Polycomb Repressive Complexes in Hox Gene Regulation: Silencing and Beyond
Gentile, C., & Kmita, M. (2020) · BioEssays · doi:10.1002/bies.201900249 · Cited by 35 · see citing works
Ramesh, V., Liu, F., Minto, M. S., Chan, U., & West, A. E. (2023) · eLife · doi:10.7554/elife.86273 · Cited by 36 · see citing works
“These loops may then 668 poise genes for enhancer activation later upon receiving a developmental stimulus [57, 58].”
Background3D genome folding in epigenetic regulation and cellular memory
Paldi, F., & Cavalli, G. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.03.001 · Cited by 34 · see citing works
Developmental Transcriptional Enhancers: A Subtle Interplay between Accessibility and Activity
Bozek, M., & Gompel, N. (2020) · BioEssays · doi:10.1002/bies.201900188 · Cited by 31 · see citing works
Fueyo, R., Iacobucci, S., Pappa, S., Estarás, C., Lois, S., Vicioso‐Mantis, M., Navarro, C., Cruz-Molina, S., Reyes, J. C., Rada-Iglesias, Á., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky093 · Cited by 31 · see citing works
“Interestingly, Neurog2(–6) enhancer deletion did not result in the activation of the gene in NSCs, supporting the idea that the poised enhancers have not repressive activity (73) as it has been previously proposed (74–76).”
BackgroundSelf-citationSchulz, M., Teissandier, A., Santaella, E. D. L. M., Armand, M., Iranzo, J., Marjou, F. E., Gestraud, P., Walter, M., Kinston, S., Göttgens, B., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01162-w · Cited by 30 · see citing works
“Co-occurrence of ATAC and H3K27ac is considered a hallmark of enhancer activity 41,42 .”
Complex regulatory networks influence pluripotent cell state transitions in human iPSCs
Arthur, T. D., Nguyen, J., D’Antonio‐Chronowska, A., Matsui, H., da Silva, N. S., Joshua, I. N., Aguiar, L. R., Arias, A. D., Benaglio, P., Berggren, W. T., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45506-6 · Cited by 30 · see citing works
“Our annotations were consistent with previous characterizations of hiPSC regulatory elements 1,38 – 40 , speci fi cally; (1) the relatively large fraction of the peaks in bivalent chromatin indicating open but inactive regulatory elements, and (2) the presence of peaks in polycomb regions.”
Chakraborty, C., Nissen, I., Vincent, C. A., Hägglund, A., Hörnblad, A., & Remeseiro, S. (2023) · Nature Communications · doi:10.1038/s41467-023-41919-x · Cited by 30 · see citing works
Dimitrova, E., Feldmann, A., van der Weide, R. H., Flach, K., Lastuvkova, A., de Wit, E., & Klose, R. J. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00840-5 · Cited by 26 · see citing works
Ling, X., Liu, X., Jiang, S., Fan, L., & Ding, J. (2022) · Cell Regeneration · doi:10.1186/s13619-022-00145-4 · Cited by 29 · see citing works
H3K27me3-mediated epigenetic regulation in pluripotency maintenance and lineage differentiation
Jiang, L., Huang, L., & Jiang, W. (2024) · Cell Insight · doi:10.1016/j.cellin.2024.100180 · Cited by 24 · see citing works
Reprogramming of the epigenome in neurodevelopmental disorders
Wilson, K., Porter, E. G. P., & Garcia, B. A. (2021) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2021.1979457 · Cited by 27 · see citing works
“Loss of PRC2 during differentiation severely compromised neural gene induction due to marked loss of bivalent enhancers (Cruz-Molina et al. 2017).”
BackgroundMLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Crump, N. T., Smith, A., Godfrey, L., Dopico-Fernandez, A. M., Denny, N., Harman, J. R., Hamley, J. C., Jackson, N., Chahrour, C., Riva, S. G., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40981-9 · Cited by 27 · see citing works
“For instance, during embryonic stem cell differentiation, pre-binding of the Polycomb Repressive Complex (PRC) is required for initial enhancer-promoter contacts 17,18 , but this does not seem to be necessary for inducing gene expression during differentiation 18 .”
A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency
Huang, X., Bashkenova, N., Hong, Y., Lyu, C., Guallar, D., Hu, Z., Malik, V., Li, D., Wang, H., Shen, X., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110928 · Cited by 26 · see citing works
Rodríguez-Carballo, E., Lopez‐Delisle, L., Yakushiji‐Kaminatsui, N., Ullate‐Agote, A., & Duboule, D. (2019) · BMC Biology · doi:10.1186/s12915-019-0677-x · Cited by 25 · see citing works
Inducible CRISPRa screen identifies putative enhancers.
Dai, Z., Li, R., Hou, Y., Li, Q., Zhao, K., Li, T., Li, M.-L., & Wu, X.-D. (2021) · Journal of genetics and genomics = Yi chuan xue bao · doi:10.1016/j.jgg.2021.06.012 · Cited by 23 · see citing works
Role of Enhancers in Development and Diseases
Maurya, S. S. (2021) · Epigenomes · doi:10.3390/epigenomes5040021 · Cited by 23 · see citing works
“Active enhancers are linked to expressed genes, while poised enhancers are always associated to developmental genes, which are inactive in embryonic stem cells or precursor cells and become expressed during different differentiation stages [22].”
BackgroundPolycomb proteins as organizers of 3D genome architecture in embryonic stem cells
Pachano, T., Crispatzu, G., & Rada-Iglesias, Á. (2019) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz022 · Cited by 24 · see citing works
Murine Models of Myelofibrosis
Jacquelin, S., Kramer, F., Mullally, A., & Lane, S. (2020) · Cancers · doi:10.3390/cancers12092381 · Cited by 23 · see citing works
“EZH2, a histone methyl transferase member of the polycomb repressive complex 2 (PRC2), is a master regulator of chromatin topology that mediates silencing through di- and trimethylation of lysine H3 (H3K27me2/3) [79,80].”
BackgroundJUN Regulation of Injury-Induced Enhancers in Schwann Cells
Ramesh, R., Manurung, Y., Ma, K. H., Blakely, T., Won, S., Moreno-Ramos, O. A., Wyatt, E. J., Awatramani, R. B., & Svaren, J. P. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.2533-21.2022 · Cited by 23 · see citing works
A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer
Szczepanski, A. P., Tsuboyama, N., Lyu, H., Wang, P., Beytullahoglu, O., Zhang, T., Singer, B. D., Yue, F., Zhao, Z., & Wang, L. (2024) · Nature Communications · doi:10.1038/s41467-024-46492-5 · Cited by 22 · see citing works
“Poised enhancers are characterized by open chromatin and marked by two opposing histone modi fi cations, namely, the active mark H3K4me1 and the repressive mark H3K27me3 19,20 .”
InfluentialEpigenetics of neural differentiation: Spotlight on enhancers
Giacoman-Lozano, M., Meléndez-Ramírez, C., Martínez-Ledesma, E., Durán, R. C., & Velasco, I. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1001701 · Cited by 22 · see citing works
“involving PRC2 is needed for the precise temporal activation of poised enhancers uponmouse ESCs differentiation into neuronal linages (Cruz-Molina et al., 2017).”
BackgroundDiverse gene regulatory mechanisms mediated by Polycomb group proteins during neural development
Tsuboi, M., Hirabayashi, Y., & Gotoh, Y. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.07.003 · Cited by 22 · see citing works
Decoding the organization, dynamics, and function of the 4D genome
Aboelnour, E., & Bonev, B. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.04.023 · Cited by 21 · see citing works
Durand, S., Bruelle, M., Bourdelais, F., Bennychen, B., Blin-Gonthier, J., Isaac, C., Huyghe, A., Martel, S., Seyve, A., Vanbelle, C., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36037-7 · Cited by 21 · see citing works
Ealo, T., Sánchez-Gaya, V., Respuela, P., Martín, M. M., Martín-Batista, E., Haro, E., & Rada-Iglesias, Á. (2024) · Nature Communications · doi:10.1038/s41467-024-51602-4 · Cited by 22 · see citing works
“Furthermore, since Asb18 is expressed at low levels in mESC (0.056 FPKM), the upregulation of Asb18 in absolute levels in Δ 3XCTCF (~5-fold) or 71Kb INV (~16-fold) cells is still very small, suggesting that the responsiveness between the Asb18 promoter and the Gbx2 enhancer might be limited 67 .”
InfluentialSelf-citationRosa, M. D., & Spivakov, M. (2020) · Nature Genetics · doi:10.1038/s41588-020-0583-8 · Cited by 19 · see citing works
- Authors
- Cruz-Molina, S., Respuela, P., Tebartz, C., Kolovos, P., Nikolic, M., Fueyo, R., van Ijcken, W. F. J., Grosveld, F., Frommolt, P., Bazzi, H., & Rada-Iglesias, A.
- Affiliations
- University of Cologne (DE)
- Erasmus MC (NL)
- Consejo Superior de Investigaciones Científicas (ES)
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 20
- Issue
- 5
- Pages
- 689-705.e9
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2594685900
- Cited by
- 240
- References
- 83
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 28 · 2023: 22 · 2022: 26 · 2021: 39 · 2020: 31 · 2019: 24 · 2018: 20 · 2017: 10
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- CMMC
- DFG (RA 2547/1-1, RA 2547/2-1, TE 1007/3-1)
- UoC Advanced Researcher Group Grant
- CECAD
- 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 › Epigenetics and DNA Methylation
- Keywords
- poised enhancers, polycomb repressive complex 2, H3K27me3, embryonic stem cell differentiation, neural induction, chromatin looping, Polycomb group proteins, pluripotent stem cells
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Fluorescent Antibody Technique, Polymerase Chain Reaction, Pluripotent Stem Cells, Chromatin Immunoprecipitation, Mice, Embryonic Stem Cells, Polycomb Repressive Complex 2
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