Long-Range Chromatin Contacts in Embryonic Stem Cells Reveal a Role for Pluripotency Factors and Polycomb Proteins in Genome Organization
Open accessAbstract
The relationship between 3D organization of the genome and gene-regulatory networks is poorly understood. Here, we examined long-range chromatin interactions genome-wide in mouse embryonic stem cells (ESCs), iPSCs, and fibroblasts and uncovered a pluripotency-specific genome organization that is gradually reestablished during reprogramming. Our data confirm that long-range chromatin interactions are primarily associated with the spatial segregation of open and closed chromatin, defining overall chromosome conformation. Additionally, we identified two further levels of genome organization in ESCs characterized by colocalization of regions with high pluripotency factor occupancy and strong enrichment for Polycomb proteins/H3K27me3, respectively. Underlining the independence of these networks and their functional relevance for genome organization, loss of the Polycomb protein Eed diminishes interactions between Polycomb-regulated regions without altering overarching chromosome conformation. Together, our data highlight a pluripotency-specific genome organization in which pluripotency factors such as Nanog and H3K27me3 occupy distinct nuclear spaces and reveal a role for cell-type-specific gene-regulatory networks in genome organization.
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Knockouts of both PRC1 and PRC2 components affect chromosomal contacts between Polycomb-bound loci.
“However, knockouts of both PRC1 and PRC2 components affect chromosomal contacts between Polycomb-bound loci [280, 360].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [360]
The Results section, “The preferential co-localization of Polycomb-enriched genomic regions is Eed-dependent” (page unavailable), reports that loss of Eed, a PRC2 component, reduces contacts between Polycomb-occupied regions in embryonic stem cells. The passages do not report a knockout of a PRC1 component, so this source supports only the PRC2 part of the claim. (LLM, conf=0.87)
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Cites
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673 · see citing works
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Dixon, J. R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., Hu, M., Liu, J. S., & Ren, B. (2012) · Nature · doi:10.1038/nature11082 · Cited by 6,829 · see citing works
Spatial partitioning of the regulatory landscape of the X-inactivation centre
Nora, E. P., Lajoie, B. R., Schulz, E. G., Giorgetti, L., Okamoto, I., Servant, N., Piolot, T., van Berkum, N. L., Meisig, J., Sedat, J., et al. (2012) · Nature · doi:10.1038/nature11049 · Cited by 2,895 · see citing works
Mediator 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
The long-range interaction landscape of gene promoters
Sanyal, A., Lajoie, B. R., Jain, G., & Dekker, J. (2012) · Nature · doi:10.1038/nature11279 · Cited by 1,489 · see citing works
Iterative correction of Hi-C data reveals hallmarks of chromosome organization
Imakaev, M., Fudenberg, G., McCord, R. P., Naumova, N., Goloborodko, A., Lajoie, B. R., Dekker, J., & Mirny, L. A. (2012) · Nature Methods · doi:10.1038/nmeth.2148 · Cited by 1,423 · see citing works
A map of the cis-regulatory sequences in the mouse genome
Shen, Y., Yue, F., McCleary, D. F., Ye, Z., Edsall, L., Kuan, S., Wagner, U., Dixon, J., Lee, L., Lobanenkov, V. V., et al. (2012) · Nature · doi:10.1038/nature11243 · Cited by 1,361 · see citing works
Flagged first, then by citations
Research works printed but not linked: 33
- Apostolou E Ferrari F Walsh RM Bar-Nur O Stadtfeld M Cheloufi S Stuart HT Polo JM Ohsumi TK Borowsky ML Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell stem cell 2013 12 699 712 23665121 PMC3725985
- Bantignies F Cavalli G Polycomb group proteins: repression in 3D. Trends in genetics: TIG 2011 27 454 464 21794944
- Bickmore WA van Steensel B Genome Architecture: Domain Organization of Interphase Chromosomes. Cell 2013 152 1270 1284 23498936
- Chamberlain SJ Yee D Magnuson T Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells 2008 26 1496 1505 18403752 PMC2630378
- de Wit E de Laat W A decade of 3C technologies: insights into nuclear organization. Genes & development 2012 26 11 24 22215806 PMC3258961
- Dekker J Rippe K Dekker M Kleckner N Capturing chromosome conformation. Science 2002 295 1306 1311 11847345
- Denholtz M Plath K Pluripotency in 3D: genome organization in pluripotent cells. Current opinion in cell biology 2012 24 793 801 23199754 PMC3540188
- Engreitz JM Pandya-Jones A McDonel P Shishkin A Sirokman K Surka C Kadri S Xing J Goren A Lander ES The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome. Science 2013 PMC3778663 23828888
- Ernst J Kellis M ChromHMM: automating chromatin-state discovery and characterization. Nature methods 2012 9 215 216 22373907 PMC3577932
- Feldman N Gerson A Fang J Li E Zhang Y Shinkai Y Cedar H Bergman Y G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat Cell Biol 2006 8 188 194 16415856
- Gibcus JH Dekker J The Hierarchy of the 3D Genome. Molecular cell 2013 49 773 782 23473598 PMC3741673
- Hakim O Sung MH Nakayamada S Voss TC Baek S Hager GL Spatial congregation of STAT binding directs selective nuclear architecture during T-cell functional differentiation. Genome research 2013 23 462 472 23212947 PMC3589535
- Hakim O Sung MH Voss TC Splinter E John S Sabo PJ Thurman RE Stamatoyannopoulos JA de Laat W Hager GL Diverse gene reprogramming events occur in the same spatial clusters of distal regulatory elements. Genome research 2011 21 697 706 21471403 PMC3083086
- Hiratani I Ryba T Itoh M Rathjen J Kulik M Papp B Fussner E Bazett-Jones DP Plath K Dalton S Genome-wide dynamics of replication timing revealed by in vitro models of mouse embryogenesis. Genome research 2010 20 155 169 19952138 PMC2813472
- Levasseur DN Wang J Dorschner MO Stamatoyannopoulos JA Orkin SH Oct4 dependence of chromatin structure within the extended Nanog locus in ES cells. Genes & development 2008 22 575 580 18283123 PMC2259027
- Lieberman-Aiden E van Berkum NL Williams L Imakaev M Ragoczy T Telling A Amit I Lajoie BR Sabo PJ Dorschner MO Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 2009 326 289 293 19815776 PMC2858594
- Montgomery ND Yee D Chen A Kalantry S Chamberlain SJ Otte AP Magnuson T The murine polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Current biology: CB 2005 15 942 947 15916951
- Nichols J Zevnik B Anastassiadis K Niwa H Klewe-Nebenius D Chambers I Scholer H Smith A Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 1998 95 379 391 9814708
- Noordermeer D de Wit E Klous P van de Werken H Simonis M Lopez-Jones M Eussen B de Klein A Singer RH de Laat W Variegated gene expression caused by cell-specific long-range DNA interactions. Nat Cell Biol 2011 13 944 951 21706023 PMC3151580
- Osborne CS Chakalova L Brown KE Carter D Horton A Debrand E Goyenechea B Mitchell JA Lopes S Reik W Active genes dynamically colocalize to shared sites of ongoing transcription. Nature genetics 2004 36 1065 1071 15361872
- Phillips-Cremins JE Sauria ME Sanyal A Gerasimova TI Lajoie BR Bell JS Ong CT Hookway TA Guo C Sun Y Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 2013 153 1281 1295 23706625 PMC3712340
- Rinn JL Kertesz M Wang JK Squazzo SL Xu X Brugmann SA Goodnough LH Helms JA Farnham PJ Segal E Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007 129 1311 1323 17604720 PMC2084369
- Schoenfelder S Sexton T Chakalova L Cope NF Horton A Andrews S Kurukuti S Mitchell JA Umlauf D Dimitrova DS Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nature genetics 2010 42 53 61 20010836 PMC3237402
- Sexton T Yaffe E Kenigsberg E Bantignies F Leblanc B Hoichman M Parrinello H Tanay A Cavalli G Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 2012 148 458 472 22265598
- Simonis M Klous P Splinter E Moshkin Y Willemsen R de Wit E van Steensel B de Laat W Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C). Nature genetics 2006 38 1348 1354 17033623
- Smallwood A Ren B Genome organization and long-range regulation of gene expression by enhancers. Current opinion in cell biology 2013 25 387 394 23465541 PMC4180870
- Splinter E de Wit E van de Werken HJ Klous P de Laat W Determining long-range chromatin interactions for selected genomic sites using 4C-seq technology: From fixation to computation. Methods 2012 22609568
- Sridharan R Tchieu J Mason MJ Yachechko R Kuoy E Horvath S Zhou Q Plath K Role of the murine reprogramming factors in the induction of pluripotency. Cell 2009 136 364 377 19167336 PMC3273494
- Takebayashi S Dileep V Ryba T Dennis JH Gilbert DM Chromatin-interaction compartment switch at developmentally regulated chromosomal domains reveals an unusual principle of chromatin folding. Proceedings of the National Academy of Sciences of the United States of America 2012 109 12574 12579 22807480 PMC3411983
- Tanizawa H Iwasaki O Tanaka A Capizzi JR Wickramasinghe P Lee M Fu Z Noma K Mapping of long-range associations throughout the fission yeast genome reveals global genome organization linked to transcriptional regulation. Nucleic acids research 2010 38 8164 8177 21030438 PMC3001101
- Wei Z Gao F Kim S Yang H Lyu J An W Wang K Lu W Klf4 organizes long-range chromosomal interactions with the oct4 locus in reprogramming and pluripotency. Cell stem cell 2013 13 36 47 23747203
- Whyte WA Orlando DA Hnisz D Abraham BJ Lin CY Kagey MH Rahl PB Lee TI Young RA Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 2013 153 307 319 23582322 PMC3653129
- Young RA Control of the embryonic stem cell state. Cell 2011 144 940 954 21414485 PMC3099475
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Smemo, S., Tena, J. J., Kim, K.-H., Gamazon, E. R., Sakabe, N. J., Gómez-Marín, C., Aneas, I., Credidio, F. L., Sobreira, D. R., Wasserman, N. F., et al. (2014) · Nature · doi:10.1038/nature13138 · Cited by 1,219 · see citing works
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Schuettengruber, B., Bourbon, H.-M., Di Croce, L., & Cavalli, G. (2017) · Cell · doi:10.1016/j.cell.2017.08.002 · Cited by 1,094 · see citing works
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Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102 · see citing works
Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes
Dowen, J. M., Fan, Z. P., Hnisz, D., Ren, G., Abraham, B. J., Zhang, L. N., Weintraub, A. S., Schuijers, J., Lee, T. I., Zhao, K., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.030 · Cited by 884 · see citing works
3D structures of individual mammalian genomes studied by single-cell Hi-C
Stevens, T. J., Lando, D., Basu, S., Atkinson, L. P., Cao, Y., Lee, S. F., Leeb, M., Wohlfahrt, K. J., Boucher, W., O’Shaughnessy-Kirwan, A., et al. (2017) · Nature · doi:10.1038/nature21429 · Cited by 832 · see citing works
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Schoenfelder, S., Furlan-Magaril, M., Mifsud, B., Tavares-Cadete, F., Sugar, R., Javierre, B.-M., Nagano, T., Katsman, Y., Sakthidevi, M., Wingett, S. W., et al. (2015) · Genome Research · doi:10.1101/gr.185272.114 · Cited by 460 · see citing works
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Gorkin, D. U., Leung, D., & Ren, B. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.05.017 · Cited by 391 · see citing works
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Cruz-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
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Rhodes, J. D. P., Feldmann, A., Hernández-Rodríguez, B., Díaz, N., Brown, J. M., Fursova, N. A., Blackledge, N. P., Prathapan, P., Dobrinic, P., Huseyin, M. K., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.057 · Cited by 187 · see citing works
Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells
Freire-Pritchett, P., Schoenfelder, S., Várnai, C., Wingett, S. W., Cairns, J., Collier, A. J., García-Vílchez, R., Furlan-Magaril, M., Osborne, C. S., Fraser, P., et al. (2017) · eLife · doi:10.7554/elife.21926 · Cited by 161 · see citing works
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Beagan, J. A., Gilgenast, T. G., Kim, J., Plona, Z., Norton, H. K., Hu, G., Hsu, S. C., Shields, E. J., Lyu, X., Apostolou, E., et al. (2016) · Cell Stem Cell · doi:10.1016/j.stem.2016.04.004 · Cited by 134 · see citing works
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Pękowska, A., Klaus, B., Xiang, W., Severino, J., Daigle, N., Klein, F. A., Oleś, M., Casellas, R., Ellenberg, J., Steinmetz, L. M., et al. (2018) · Cell Systems · doi:10.1016/j.cels.2018.09.003 · Cited by 74 · see citing works
Transcriptional 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
- Authors
- Denholtz, M., Bonora, G., Chronis, C., Splinter, E., de Laat, W., Ernst, J., Pellegrini, M., & Plath, K.
- Affiliations
- University of California, Los Angeles (US)
- University Medical Center Utrecht (NL)
- Corresponding author
- Pellegrini, Matteo
- Plath, Kathrin
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 13
- Issue
- 5
- Pages
- 602-616
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC3825755
- OpenAlex
- W2017298168
- Cited by
- 274
- References
- 7
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 16 · 2023: 8 · 2022: 21 · 2021: 25 · 2020: 22 · 2019: 41 · 2018: 23 · 2017: 26 · 2016: 29 · 2015: 27 · 2014: 23
- FWCI
- 11.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Science Foundation (1066293)
- Aspen Center for Physics (1066293)
- Leukemia and Lymphoma Research
- National Institutes of Health (1dp2od001686-01)
- National Institute of General Medical Sciences (P01GM081621, P01GM099134)
- David Geffen School of Medicine, University of California, Los Angeles
- FP7 Ideas: European Research Council (209700)
- 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
- long-range chromatin interactions, 3D genome organization, mouse embryonic stem cells, induced pluripotent stem cells, pluripotency factors, Polycomb group proteins, H3K27me3, EED, Nanog, reprogramming, gene regulatory networks, chromosome conformation, fibroblasts
- MeSH terms
- Animals, Chromatin, Histones, Protein Binding, In Situ Hybridization, Fluorescence, Mice, Embryonic Stem Cells, Polycomb-Group Proteins
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