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• W3109612977 abstract "Higher-order chromatin structure is tightly linked to gene expression and therefore cell identity. In recent years, the chromatin landscape of pluripotent stem cells has become better characterized, and unique features at various architectural levels have been revealed. However, the mechanisms that govern establishment and maintenance of these topological characteristics and the temporal and functional relationships with transcriptional or epigenetic features are still areas of intense study. Here, we will discuss progress and limitations of our current understanding regarding how the 3D chromatin topology of pluripotent stem cells is established during somatic cell reprogramming and maintained during cell division. We will also discuss evidence and theories about the driving forces of topological reorganization and the functional links with key features and properties of pluripotent stem cell identity. Higher-order chromatin structure is tightly linked to gene expression and therefore cell identity. In recent years, the chromatin landscape of pluripotent stem cells has become better characterized, and unique features at various architectural levels have been revealed. However, the mechanisms that govern establishment and maintenance of these topological characteristics and the temporal and functional relationships with transcriptional or epigenetic features are still areas of intense study. Here, we will discuss progress and limitations of our current understanding regarding how the 3D chromatin topology of pluripotent stem cells is established during somatic cell reprogramming and maintained during cell division. We will also discuss evidence and theories about the driving forces of topological reorganization and the functional links with key features and properties of pluripotent stem cell identity. The three-dimensional (3D) organization of the genome has been shown to have major implications for gene regulation and therefore cell identity. Over the last three decades, technological advancements in microscopy and genome-wide chromatin topology assays (Kempfer and Pombo, 2020Kempfer R. Pombo A. Methods for mapping 3D chromosome architecture.Nat. Rev. Genet. 2020; 21: 207-226Crossref PubMed Scopus (34) Google Scholar) uncovered a hierarchical 3D genomic organization ranging from whole chromosome territories to (sub)megabase structures and fine-scale chromatin loops (Gibcus and Dekker, 2013Gibcus J.H. Dekker J. The hierarchy of the 3D genome.Mol. Cell. 2013; 49: 773-782Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar; Yu and Ren, 2017Yu M. Ren B. The three-dimensional organization of mammalian genomes.Annu. Rev. Cell Dev. Biol. 2017; 33: 265-289Crossref PubMed Scopus (94) Google Scholar). Individual chromosomes reside in discrete regions of the nucleus called chromosome territories (Cremer and Cremer, 2001Cremer T. Cremer C. Chromosome territories, nuclear architecture and gene regulation in mammalian cells.Nat. Rev. Genet. 2001; 2: 292-301Crossref PubMed Scopus (1512) Google Scholar). Within each chromosome, euchromatic and heterochromatic regions segregate into different subnuclear compartments named A and B, respectively (Lieberman-Aiden et al., 2009Lieberman-Aiden E. van Berkum N.L. Williams L. Imakaev M. Ragoczy T. Telling A. Amit I. Lajoie B.R. Sabo P.J. Dorschner M.O. et al.Comprehensive mapping of long-range interactions reveals folding principles of the human genome.Science. 2009; 326: 289-293Crossref PubMed Scopus (3498) Google Scholar; Wang et al., 2016Wang S. Su J.H. Beliveau B.J. Bintu B. Moffitt J.R. Wu C.T. Zhuang X. Spatial organization of chromatin domains and compartments in single chromosomes.Science. 2016; 353: 598-602Crossref PubMed Google Scholar). The A compartments are gene rich, accessible, transcriptionally active, and largely occupy the nuclear interior, while B compartments are gene poor, inactive, and inaccessible regions, located at the nuclear periphery and overlapping with lamina-associated domains (LADs) (Guelen et al., 2008Guelen L. Pagie L. Brasset E. Meuleman W. Faza M.B. Talhout W. Eussen B.H. de Klein A. Wessels L. de Laat W. et al.Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions.Nature. 2008; 453: 948-951Crossref PubMed Scopus (1106) Google Scholar; Haarhuis et al., 2017Haarhuis J.H.I. van der Weide R.H. Blomen V.A. Yanez-Cuna J.O. Amendola M. van Ruiten M.S. Krijger P.H.L. Teunissen H. Medema R.H. van Steensel B. et al.The cohesin release factor WAPL restricts chromatin loop extension.Cell. 2017; 169: 693-707.e14Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). Due to their association with transcriptional activity, compartments are distinct across cell types (Dixon et al., 2012Dixon J.R. Selvaraj S. Yue F. Kim A. Li Y. Shen Y. Hu M. Liu J.S. Ren B. Topological domains in mammalian genomes identified by analysis of chromatin interactions.Nature. 2012; 485: 376-380Crossref PubMed Scopus (2874) Google Scholar, Dixon et al., 2015Dixon J.R. Jung I. Selvaraj S. Shen Y. Antosiewicz-Bourget J.E. Lee A.Y. Ye Z. Kim A. Rajagopal N. Xie W. et al.Chromatin architecture reorganization during stem cell differentiation.Nature. 2015; 518: 331-336Crossref PubMed Scopus (649) Google Scholar; Takebayashi et al., 2012Takebayashi S.-i. Dileep V. Ryba T. Dennis J.H. Gilbert D.M. Chromatin-interaction compartment switch at developmentally regulated chromosomal domains reveals an unusual principle of chromatin folding.Proc. Natl. Acad. Sci. U S A. 2012; 109: 12574-12579Crossref PubMed Scopus (46) Google Scholar). At (sub)megabase scale, we detect self-associating domains, known as topologically associating domains (TADs) (Dixon et al., 2016Dixon J.R. Gorkin D.U. Ren B. Chromatin domains: the unit of chromosome organization.Mol. Cell. 2016; 62: 668-680Abstract Full Text Full Text PDF PubMed Google Scholar; Nora et al., 2017Nora E.P. Goloborodko A. Valton A.L. Gibcus J.H. Uebersohn A. Abdennur N. Dekker J. Mirny L.A. Bruneau B.G. Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization.Cell. 2017; 169: 930-944.e22Abstract Full Text Full Text PDF PubMed Scopus (466) Google Scholar; Sexton et al., 2012Sexton 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: 458-472Abstract Full Text Full Text PDF PubMed Scopus (1006) Google Scholar) or contact domains (Tang et al., 2015Tang Z. Luo O.J. Li X. Zheng M. Zhu J.J. Szalaj P. Trzaskoma P. Magalska A. Wlodarczyk J. Ruszczycki B. et al.CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription.Cell. 2015; 163: 1611-1627Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar). These are found in both A and B compartments and are demarcated by insulating boundaries, which prevent interactions with neighboring TADs. While TADs are largely conserved among cell types, the insulation strength of TAD boundaries and patterns of intra-TAD interactions can vary (Crane et al., 2015Crane E. Bian Q. McCord R.P. Lajoie B.R. Wheeler B.S. Ralston E.J. Uzawa S. Dekker J. Meyer B.J. Condensin-driven remodelling of X chromosome topology during dosage compensation.Nature. 2015; 523: 240-244Crossref PubMed Scopus (273) Google Scholar). Sub-TADs, or smaller insulated neighborhoods nested inside larger ones, have also been described (Phillips-Cremins et al., 2013Phillips-Cremins J.E. Sauria M.E. Sanyal A. Gerasimova T.I. Lajoie B.R. Bell J.S. Ong C.T. Hookway T.A. Guo C. Sun Y. et al.Architectural protein subclasses shape 3D organization of genomes during lineage commitment.Cell. 2013; 153: 1281-1295Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar; Rao et al., 2014Rao S.S.P. Huntley M.H. Durand N.C. Stamenova E.K. Bochkov I.D. Robinson J.T. Sanborn A.L. Machol I. Omer A.D. Lander E.S. et al.A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.Cell. 2014; 159: 1665-1680Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar). Although current nomenclature in the field is rather confusing (Dixon et al., 2016Dixon J.R. Gorkin D.U. Ren B. Chromatin domains: the unit of chromosome organization.Mol. Cell. 2016; 62: 668-680Abstract Full Text Full Text PDF PubMed Google Scholar; Schoenfelder and Fraser, 2019Schoenfelder S. Fraser P. Long-range enhancer–promoter contacts in gene expression control.Nat. Rev. Genet. 2019; 55: 1Google Scholar), studies have provided strong evidence for the role of TADs and insulated neighborhoods in gene expression by restricting enhancer activity and specificity (Dowen et al., 2014Dowen J.M. Fan Z.P. Hnisz D. Ren G. Abraham B.J. Zhang L.N. Weintraub A.S. Schujiers J. Lee T.I. Zhao K. et al.Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes.Cell. 2014; 159: 374-387Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar; Lupiáñez et al., 2015Lupiáñez D.G. Kraft K. Heinrich V. Krawitz P. Brancati F. Klopocki E. Horn D. Kayserili H. Opitz J.M. Laxova R. et al.Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.Cell. 2015; 161: 1012-1025Abstract Full Text Full Text PDF PubMed Scopus (781) Google Scholar; Sun et al., 2019Sun F. Chronis C. Kronenberg M. Chen X.F. Su T. Lay F.D. Plath K. Kurdistani S.K. Carey M.F. Promoter-enhancer communication occurs primarily within insulated neighborhoods.Mol. Cell. 2019; 73: 250-263 e255Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Finally, at the finest level of architectural organization there are pairwise chromatin contacts between distal genomic loci, ranging from few kilobase pairs (kb) to several megabases (Mb) of linear distance. Different types of long-range genomic interactions have been identified based on the mediating protein factors and their potential impact on gene expression (Cheutin and Cavalli, 2019Cheutin T. Cavalli G. The multiscale effects of polycomb mechanisms on 3D chromatin folding.Crit. Rev. Biochem. Mol. Biol. 2019; 54: 399-417Crossref PubMed Scopus (1) Google Scholar; Schoenfelder and Fraser, 2019Schoenfelder S. Fraser P. Long-range enhancer–promoter contacts in gene expression control.Nat. Rev. Genet. 2019; 55: 1Google Scholar; van Steensel and Furlong, 2019van Steensel B. Furlong E.E.M. The role of transcription in shaping the spatial organization of the genome.Nat. Rev. Mol. Cell Biol. 2019; 20: 327-337Crossref PubMed Scopus (47) Google Scholar). These include active contacts between cis-regulatory elements (enhancer-promoter), Polycomb-mediated repressive/poising interactions (Cheutin and Cavalli, 2019Cheutin T. Cavalli G. The multiscale effects of polycomb mechanisms on 3D chromatin folding.Crit. Rev. Biochem. Mol. Biol. 2019; 54: 399-417Crossref PubMed Scopus (1) Google Scholar; Denholtz et al., 2013Denholtz M. Bonora G. Chronis C. Splinter E. de Laat W. Ernst J. Pellegrini M. Plath K. Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization.Cell Stem Cell. 2013; 13: 602-616Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar; Eagen et al., 2017Eagen K.P. Aiden E.L. Kornberg R.D. Polycomb-mediated chromatin loops revealed by a subkilobase-resolution chromatin interaction map.Proc. Natl. Acad. Sci. U S A. 2017; 114: 8764-8769Crossref PubMed Scopus (51) Google Scholar; Schoenfelder et al., 2015bSchoenfelder S. Sugar R. Dimond A. Javierre B.M. Armstrong H. Mifsud B. Dimitrova E. Matheson L. Tavares-Cadete F. Furlan-Magaril M. et al.Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome.Nat. Genet. 2015; 47: 1179-1186Crossref PubMed Scopus (165) Google Scholar), and CTCF/Cohesin structural loops (Handoko et al., 2011Handoko L. Xu H. Li G. Ngan C.Y. Chew E. Schnapp M. Lee C.W.H. Ye C. Ping J.L.H. Mulawadi F. et al.CTCF-mediated functional chromatin interactome in pluripotent cells.Nat. Genet. 2011; 43: 630-638Crossref PubMed Scopus (449) Google Scholar; Robson et al., 2019Robson M.I. Ringel A.R. Mundlos S. Regulatory landscaping: how enhancer-promoter communication is sculpted in 3D.Mol. Cell. 2019; 74: 1110-1122Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Although structural loops are largely conserved among cell types, activating and repressive/poised contacts can be reorganized during cell fate transitions (Penalosa-Ruiz et al., 2019Penalosa-Ruiz G. Bright A.R. Mulder K.W. Veenstra G.J.C. The interplay of chromatin and transcription factors during cell fate transitions in development and reprogramming.Biochim. Biophys. Acta Gene Regul. Mech. 2019; 1862: 194407Crossref PubMed Scopus (1) Google Scholar). Two main forces are thought to work together and against each other to shape the layers of the 3D genome: loop extrusion and compartmental segregation, as extensively reviewed recently (Beagan and Phillips-Cremins, 2020Beagan J.A. Phillips-Cremins J.E. On the existence and functionality of topologically associating domains.Nat. Genet. 2020; 52: 8-16Crossref PubMed Scopus (23) Google Scholar; Nuebler et al., 2018Nuebler J. Fudenberg G. Imakaev M. Abdennur N. Mirny L.A. Chromatin organization by an interplay of loop extrusion and compartmental segregation.Proc. Natl. Acad. Sci. U S A. 2018; 115: E6697-E6706Crossref PubMed Scopus (139) Google Scholar; Rada-Iglesias et al., 2018Rada-Iglesias A. Grosveld F.G. Papantonis A. Forces driving the three-dimensional folding of eukaryotic genomes.Mol. Syst. Biol. 2018; : e8214PubMed Google Scholar; Rowley et al., 2017Rowley M.J. Nichols M.H. Lyu X. Ando-Kuri M. Rivera I.S.M. Hermetz K. Wang P. Ruan Y. Corces V.G. Evolutionarily conserved principles predict 3D chromatin organization.Mol. Cell. 2017; 67: 837-852.e7Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). In loop extrusion, the loaded Cohesin complex keeps sliding/extruding DNA through its ring until it encounters convergently oriented CTCF sites (Fudenberg et al., 2016Fudenberg G. Imakaev M. Lu C. Goloborodko A. Abdennur N. Mirny L.A. formation of chromosomal domains by loop extrusion.Cell Rep. 2016; 15: 2038-2049Abstract Full Text Full Text PDF PubMed Google Scholar; Sanborn et al., 2015Sanborn A.L. Rao S.S. Huang S.C. Durand N.C. Huntley M.H. Jewett A.I. Bochkov I.D. Chinnappan D. Cutkosky A. Li J. et al.Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes.Proc. Natl. Acad. Sci. U S A. 2015; 112: E6456-E6465Crossref PubMed Scopus (612) Google Scholar). Loop extrusion is thus responsible for the formation of CTCF/Cohesin-mediated loops, TADs, and sub-TADs (Beagan and Phillips-Cremins, 2020Beagan J.A. Phillips-Cremins J.E. On the existence and functionality of topologically associating domains.Nat. Genet. 2020; 52: 8-16Crossref PubMed Scopus (23) Google Scholar), as well as the recently described “stripes” or “flames” (Fudenberg et al., 2016Fudenberg G. Imakaev M. Lu C. Goloborodko A. Abdennur N. Mirny L.A. formation of chromosomal domains by loop extrusion.Cell Rep. 2016; 15: 2038-2049Abstract Full Text Full Text PDF PubMed Google Scholar; Hsieh et al., 2020Hsieh T.-H.S. Cattoglio C. Slobodyanyuk E. Hansen A.S. Rando O.J. Tjian R. Darzacq X. Resolving the 3D landscape of transcription-linked mammalian chromatin folding.Mol. Cell. 2020; 78: 539-553.e8Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar; Rao et al., 2014Rao S.S.P. Huntley M.H. Durand N.C. Stamenova E.K. Bochkov I.D. Robinson J.T. Sanborn A.L. Machol I. Omer A.D. Lander E.S. et al.A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.Cell. 2014; 159: 1665-1680Abstract Full Text Full Text PDF PubMed Scopus (2241) Google Scholar; Vian et al., 2018Vian L. Pekowska A. Rao S.S.P. Kieffer-Kwon K.R. Jung S. Baranello L. Huang S.C. El Khattabi L. Dose M. Pruett N. et al.The energetics and physiological impact of cohesin extrusion.Cell. 2018; 173: 1165-1178.e20Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). On the other hand, A and B compartmentalization occurs through increased “self-attraction”/affinity among chromatin loci with similar transcriptional and chromatin states, such as homotypic histone modifications and transcription factors (TFs)/cofactors. Liquid/liquid-phase separation is one mechanism of chromatin self-organization/segregation (Palikyras and Papantonis, 2019Palikyras S. Papantonis A. Modes of phase separation affecting chromatin regulation.Open Biol. 2019; 9: 190167Crossref PubMed Scopus (5) Google Scholar), and it results in the formation of subnuclear droplet-like condensates or membraneless organelles, such as nucleoli or nuclear speckles. A large number of TFs (Boija et al., 2018Boija A. Klein I.A. Sabari B.R. Dall'Agnese A. Coffey E.L. Zamudio A.V. Li C.H. Shrinivas K. Manteiga J.C. Hannett N.M. et al.Transcription factors activate genes through the phase-separation capacity of their activation domains.Cell. 2018; 175: 1842-1855.e16Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar; Chong et al., 2018Chong S. Dugast-Darzacq C. Liu Z. Dong P. Dailey G.M. Cattoglio C. Heckert A. Banala S. Lavis L. 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Grube V. Cisse I.I. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates.Science. 2018; : eaar4199Google Scholar; Zamudio et al., 2019Zamudio A.V. Dall'Agnese A. Henninger J.E. Manteiga J.C. Afeyan L.K. Hannett N.M. Coffey E.L. Li C.H. Oksuz O. Sabari B.R. et al.Mediator condensates localize signaling factors to key cell identity genes.Mol. Cell. 2019; 76: 753-766.e6Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar) have been reported to form large nuclear condensates, which may mediate activating or repressive chromatin contacts in a loop-extrusion-independent manner. There is increasing evidence for the distinct but interconnected nature of these two guiding mechanisms, as knock-down or degradation of CTCF or Cohesin subunits disrupts TADs, stripes, and structural chromatin loops but has minimal effect on transcription and even reinforces compartmentalization (Haarhuis et al., 2017Haarhuis J.H.I. van der Weide R.H. Blomen V.A. 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Pluripotent stem cells (PSCs) are endowed with the remarkable capacity to self-renew indefinitely in culture (self-renewal) while preserving their potential to differentiate into all somatic cell types upon proper stimulation in vitro or upon blastocyst injection in vivo (pluripotency) (Evans, 2011Evans M. Discovering pluripotency: 30 years of mouse embryonic stem cells.Nat. Rev. Mol. Cell Biol. 2011; 12: 680-686Crossref PubMed Scopus (109) Google Scholar; Tabar and Studer, 2014Tabar V. Studer L. Pluripotent stem cells in regenerative medicine: challenges and recent progress.Nat. Rev. Genet. 2014; 15: 82-92Crossref PubMed Scopus (282) Google Scholar). PSCs encompass both embryonic stem cells (ESCs), derived from early embryos, and induced PSCs (iPSCs), generated through somatic cell reprogramming (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (15999) Google Scholar). The cellular properties of PSCs are supported by their unique epigenetic landscape, characterized by overall low levels of DNA methylation and heterochromatin marks and a prevalence of Polycomb-dependent repressive (H3K27me3) or bivalent (H3K4me3/H3K27me3) chromatin around lineage-related genes (extensively reviewed; see Di Giammartino and Apostolou, 2016Di Giammartino D.C. Apostolou E. The chromatin signature of pluripotency: establishment and maintenance.Curr. Stem Cell Rep. 2016; 2: 255-262Crossref PubMed Scopus (8) Google Scholar; Harikumar and Meshorer, 2015Harikumar A. Meshorer E. Chromatin remodeling and bivalent histone modifications in embryonic stem cells.EMBO Rep. 2015; 16: 1609-1619Crossref PubMed Scopus (81) Google Scholar; Papp and Plath, 2013Papp B. Plath K. Epigenetics of reprogramming to induced pluripotency.Cell. 2013; 152: 1324-1343Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). This “open” and permissive chromatin environment becomes progressively restrained during differentiation as potency decreases (Sexton and Cavalli, 2015Sexton T. Cavalli G. The role of chromosome domains in shaping the functional genome.Cell. 2015; 160: 1049-1059Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar), and must be reset during reprogramming. The 3D genomic organization of PSCs is also characterized by distinct architectural features, such as the prevalence of A versus B compartments and the presence of PRC1/2-driven long-range interactions (Denholtz et al., 2013Denholtz M. Bonora G. Chronis C. Splinter E. de Laat W. Ernst J. Pellegrini M. Plath K. Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization.Cell Stem Cell. 2013; 13: 602-616Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar; Joshi et al., 2015Joshi O. Wang S.Y. Kuznetsova T. Atlasi Y. Peng T. Fabre P.J. Habibi E. Shaik J. Saeed S. Handoko L. et al.Dynamic reorganization of extremely long-range promoter-promoter interactions between two states of pluripotency.Cell Stem Cell. 2015; 17: 748-757Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar; Schoenfelder et al., 2015bSchoenfelder S. Sugar R. Dimond A. Javierre B.M. Armstrong H. Mifsud B. Dimitrova E. Matheson L. Tavares-Cadete F. Furlan-Magaril M. et al.Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome.Nat. Genet. 2015; 47: 1179-1186Crossref PubMed Scopus (165) Google Scholar). Importantly, the 3D chromatin features of PSCs have largely been characterized in established, asynchronously cycling PSCs and often in comparison with other steady-state somatic cell types. In the following sections we will discuss recent work that sheds light on the dynamic nature of these features and particularly on how PSC-specific 3D chromatin landscape is established upon acquisition of pluripotency and propagated during cell division (Figure 1). We will particularly focus on findings from mouse naive PSCs that represent a pre-implantation pluripotent state, unless otherwise specified. Our goal is to highlight key factors and forces involved in building and maintaining PSC fate through reprogramming and self-renewal, respectively. Since the first derivation of iPSCs by Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (15999) Google Scholar, cellular reprogramming has proved to be a powerful system to study mechanisms that dictate cell fate changes (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (15999) Google Scholar). Ectopic expression of four TFs (OCT4, SOX2, KLF4, and c-MYC) can convert somatic cells into iPSCs with the genetic and epigenetic characteristics of stem cells, capable of self-renewing and differentiating into all germ layers in vivo. As somatic cells reprogram, they undergo cellular, transcriptional, metabolic, and epigenetic changes that result in erasure of the somatic program and establishment of pluripotency-defining properties (Apostolou and Hochedlinger, 2013Apostolou E. Hochedlinger K. Chromatin dynamics during cellular reprogramming.Nature. 2013; 502: 462-471Crossref PubMed Scopus (238) Google Scholar; Brumbaugh et al., 2019Brumbaugh J. Di Stefano B. Hochedlinger K. Reprogramming: identifying the mechanisms that safeguard cell identity.Development. 2019; 146: dev182170Crossref PubMed Scopus (3) Google Scholar; Papp and Plath, 2013Papp B. Plath K. Epigenetics of reprogramming to induced pluripotency.Cell. 2013; 152: 1324-1343Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). 3D chromatin architecture is also drastically reorganized during reprogramming, as shown by comparing various somatic cells with the resultant iPSCs, through profiling long-range interactions around specific loci (4C-seq or 5C) (Apostolou et al., 2013Apostolou E. Ferrari F. Walsh R.M. Bar-Nur O. Stadtfeld M. Cheloufi S. Stuart H.T. Polo J.M. Ohsumi T.K. Borowsky M.L. et al.Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming.Cell Stem Cell. 2013; 12: 699-712Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar; Beagan et al., 2016Beagan 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.Local genome topology can exhibit an incompletely rewired 3D-folding state during somatic cell reprogramming.Cell Stem Cell. 2016; 18: 611-624Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar; Denholtz et al., 2013Denholtz M. Bonora G. Chronis C. Splinter E. de Laat W. Ernst J. Pellegrini M. Plath K. Long-range chromatin contacts in embryonic stem cells reveal a role for pluripotency factors and polycomb proteins in genome organization.Cell Stem Cell. 2013; 13: 602-616Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar; Wei et al., 2013Wei 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: 36-47Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar) or in a genome-wide fashion by Hi-C (Krijger et al., 2016Krijger P.H.L. Di Stefano B. de Wit E. Limone F. van Oevelen C. de Laat W. Graf T. Cell-of-Origin-Specific 3D genome structure acquired during somatic cell reprogramming.Cell Stem Cell. 2016; 18: 597-610Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Although most of these studies examined 3D chromatin architecture between start and endpoint fates, our review will focus on recent work that has begun to characterize the dynamic topological reorganization during reprogramming as well as underlying mechanisms and temporal associations with transcriptional and epigenetic changes. Reprogramming of multiple different mouse somatic tissue types (pre-B cells, macrophages, neural stem cells, mouse embryonic fibroblasts (MEFs)) resulted in iPSCs with 99% compartment similarity to one another and to naive ESCs (Krijger et al., 2016Krijger P.H.L. Di Stefano B. de Wit E. Limone F. van Oevelen C. de Laat W. Graf T. Cell-of-Origin-Specific 3D genome structure acquired during somatic cell reprogramming.Cell Stem Cell. 2016; 18: 597-610Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). This highlights" @default.
• W3109612977 created "2020-12-07" @default.
• W3109612977 creator A5017913027 @default.
• W3109612977 creator A5058954420 @default.
• W3109612977 creator A5065976197 @default.
• W3109612977 date "2020-12-01" @default.
• W3109612977 modified "2023-10-14" @default.
• W3109612977 title "Dynamic 3D Chromatin Reorganization during Establishment and Maintenance of Pluripotency" @default.
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