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• W2294365510 abstract "•The 3D genome topology of four somatic cell types varies greatly and differs from ESCs•The 3D genomes of iPSCs from different founders and of ESCs are overall highly similar•Early-passage iPSCs show subtle but reproducible founder-dependent 3D differences•The distinctive topology features of iPSCs are acquired during reprogramming Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic stem-cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable recognition of their cell of origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin-dependent gene expression patterns. Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic stem-cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable recognition of their cell of origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin-dependent gene expression patterns. Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by overexpression of the transcription factors OCT4, SOX2, KLF4, and MYC (OSKM) (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 (18864) Google Scholar). Regardless of tissue origin, IPSCs possess full developmental potential in vitro, form teratomas in vivo, and are even capable of generating “all-iPSC mice” after injection into tetraploid blastocysts (Zhao et al., 2009Zhao X.Y. Li W. Lv Z. Liu L. Tong M. Hai T. Hao J. Guo C.L. Ma Q.W. Wang L. et al.iPS cells produce viable mice through tetraploid complementation.Nature. 2009; 461: 86-90Crossref PubMed Scopus (642) Google Scholar). Their ability to contribute to all tissues makes iPSCs attractive for disease modeling and for regenerative medicine. Recently, it was reported that the differentiation propensity of iPSCs reflects the tissue of origin, such that neural-derived iPSCs more readily differentiate into neurons, and blood-cell-derived iPSCs are biased toward the hematopoietic lineage (Bar-Nur et al., 2011Bar-Nur O. Russ H.A. Efrat S. Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells.Cell Stem Cell. 2011; 9: 17-23Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, Kim et al., 2010Kim K. Doi A. Wen B. Ng K. Zhao R. Cahan P. Kim J. Aryee M.J. Ji H. Ehrlich L.I. et al.Epigenetic memory in induced pluripotent stem cells.Nature. 2010; 467: 285-290Crossref PubMed Scopus (1714) Google Scholar, Nishino et al., 2011Nishino K. Toyoda M. Yamazaki-Inoue M. Fukawatase Y. Chikazawa E. Sakaguchi H. Akutsu H. Umezawa A. DNA methylation dynamics in human induced pluripotent stem cells over time.PLoS Genet. 2011; 7: e1002085Crossref PubMed Scopus (229) Google Scholar, Polo et al., 2010Polo J.M. Liu S. Figueroa M.E. Kulalert W. Eminli S. Tan K.Y. Apostolou E. Stadtfeld M. Li Y. Shioda T. et al.Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.Nat. Biotechnol. 2010; 28: 848-855Crossref PubMed Scopus (943) Google Scholar). This tissue of origin memory has been shown to be associated with differences in epigenetic features. Residual DNA methylation marks were found at promoters in early iPSCs, presumably stably silencing genes that act in specifying lineages other than the donor cell type (Kim et al., 2010Kim K. Doi A. Wen B. Ng K. Zhao R. Cahan P. Kim J. Aryee M.J. Ji H. Ehrlich L.I. et al.Epigenetic memory in induced pluripotent stem cells.Nature. 2010; 467: 285-290Crossref PubMed Scopus (1714) Google Scholar). Early passage iPSCs obtained from different cell types were also found to have distinct gene expression profiles. Some of the distinguishing genes appeared to show residual cell-of-origin-specific transcription, which was interpreted to reflect memory of the transcriptional status in founder cells (Polo et al., 2010Polo J.M. Liu S. Figueroa M.E. Kulalert W. Eminli S. Tan K.Y. Apostolou E. Stadtfeld M. Li Y. Shioda T. et al.Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.Nat. Biotechnol. 2010; 28: 848-855Crossref PubMed Scopus (943) Google Scholar). The founder-dependent transcription and DNA methylation profiles were lost upon prolonged passaging of the iPSCs or after treatment with chromatin-modifying drugs (Kim et al., 2010Kim K. Doi A. Wen B. Ng K. Zhao R. Cahan P. Kim J. Aryee M.J. Ji H. Ehrlich L.I. et al.Epigenetic memory in induced pluripotent stem cells.Nature. 2010; 467: 285-290Crossref PubMed Scopus (1714) Google Scholar, Polo et al., 2010Polo J.M. Liu S. Figueroa M.E. Kulalert W. Eminli S. Tan K.Y. Apostolou E. Stadtfeld M. Li Y. Shioda T. et al.Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.Nat. Biotechnol. 2010; 28: 848-855Crossref PubMed Scopus (943) Google Scholar). Different cell types also show distinct 3D chromatin structures (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 (944) Google Scholar, Rao et al., 2014Rao S.S. 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. Aiden E.L. 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 (3598) Google Scholar), and genome topology is increasingly appreciated as an important contributor to genome functioning. Chromosomes can be subdivided into topologically associated domains (TADs), structural units within which sequences preferentially contact each other (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 (3955) Google Scholar, Nora et al., 2012Nora 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.Spatial partitioning of the regulatory landscape of the X-inactivation centre.Nature. 2012; 485: 381-385Crossref PubMed Scopus (1807) 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 (1288) Google Scholar). TADs serve to physically restrain interactions of enhancers with their target gene promoters (Nora et al., 2012Nora 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.Spatial partitioning of the regulatory landscape of the X-inactivation centre.Nature. 2012; 485: 381-385Crossref PubMed Scopus (1807) Google Scholar). TAD organization is relatively stable during development, but contacts within TADs can dynamically change between cell types (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 (802) Google Scholar). While some enhancer-promoter contacts seem tissue invariant, others are specifically established during differentiation, contributing to tissue-specific transcription programs (de Laat and Duboule, 2013de Laat W. Duboule D. Topology of mammalian developmental enhancers and their regulatory landscapes.Nature. 2013; 502: 499-506Crossref PubMed Scopus (343) Google Scholar, Rao et al., 2014Rao S.S. 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. Aiden E.L. 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 (3598) Google Scholar). To what degree this is also true for higher levels of structural chromatin organization is not fully understood yet, but some TADs switch between genomic neighborhoods, or compartments, in a cell-type-dependent manner (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 (944) Google Scholar, Rao et al., 2014Rao S.S. 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. Aiden E.L. 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 (3598) Google Scholar). The genome of embryonic stem cells (ESCs), for example, uniquely brings together distal chromosomal regions that are densely packed with pluripotency factors, which creates a configuration proposed to contribute to maintenance of pluripotency (de Wit et al., 2013de Wit E. Bouwman B.A. Zhu Y. Klous P. Splinter E. Verstegen M.J. Krijger P.H. Festuccia N. Nora E.P. Welling M. et al.The pluripotent genome in three dimensions is shaped around pluripotency factors.Nature. 2013; 501: 227-231Crossref PubMed Scopus (204) Google Scholar). Furthermore, it has been shown that the pluripotency genes Nanog and Oct4 make specific long-range interactions in ESC and iPSCs, which are lost during differentiation (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 (162) 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 (201) 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 (161) Google Scholar). However, little is known to what extent the overall 3D genome of somatic cells and their iPS derivatives differ, how stable such differences are, and how similar the 3D configurations of iPSC and ESC genomes are. Here we show that somatic cell reprogramming is accompanied by massive changes in genome topology, which, irrespective of the cell type of origin, converge on the 3D structure of the pluripotent genome. Despite this, distinct topological features separate early passage iPSCs according to their cell type of origin, and these differences seem to be acquired during reprogramming in a founder-cell-dependent manner. To study how reprogramming of somatic cells affects nuclear organization, we used reprogrammable, OSKM-inducible, mice (Carey et al., 2010Carey B.W. Markoulaki S. Beard C. Hanna J. Jaenisch R. Single-gene transgenic mouse strains for reprogramming adult somatic cells.Nat. Methods. 2010; 7: 56-59Crossref PubMed Scopus (461) Google Scholar). We generated three independent iPS cell lines each from four different founder cell types, i.e., pre-B cells, bone-marrow-derived macrophages (MΦ), neural stem cells (NSCs), and mouse embryonic fibroblasts (MEFs) (Figure 1A). iPSCs were established after picking of doxy-independent colonies at day 20 of reprogramming (15 days of reprogramming in the presence of doxy + 5 days without doxy) and were expanded for an additional 3 passages or 20 passages to obtain early (p3) and late (p20) passage iPS lines, respectively. Both p3 and p20 passage iPSC lines showed characteristic ESC-like morphology, expressed markers of pluripotency, as shown by immunofluorescence and fluorescence-activated cell sorting (FACS), and could be maintained in a transgene-independent manner (Figures 1B, 2A , and S1A). Furthermore, p3 iPSCs derived from each cell type gave rise to chimeras upon blastocyst injection (Figure 1C). Importantly, embryoid bodies (EBs) obtained from the various p3 iPSC lines showed a differentiation bias toward the cell type of origin (Figure S1B). EBs derived from pre-B-iPSCs and MΦ-iPSCs showed higher expression of the hematopoietic-associated genes Cd45, Cd41, Itgam (Mac-1), and Hoxb4, while the neuronal-associated genes Nestin and Pax6 were more highly expressed in EBs derived from NSC-iPSCs. In contrast, the endoderm associated gene Sox7 showed no such a bias (Figure S1C). The blood and neural origin bias was lost in p20 iPSCs (Figure S1D). These findings confirm the tissue-of-origin memory of early passage iPSCs described previously (Bar-Nur et al., 2011Bar-Nur O. Russ H.A. Efrat S. Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells.Cell Stem Cell. 2011; 9: 17-23Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar, Kim et al., 2010Kim K. Doi A. Wen B. Ng K. Zhao R. Cahan P. Kim J. Aryee M.J. Ji H. Ehrlich L.I. et al.Epigenetic memory in induced pluripotent stem cells.Nature. 2010; 467: 285-290Crossref PubMed Scopus (1714) Google Scholar, Polo et al., 2010Polo J.M. Liu S. Figueroa M.E. Kulalert W. Eminli S. Tan K.Y. Apostolou E. Stadtfeld M. Li Y. Shioda T. et al.Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.Nat. Biotechnol. 2010; 28: 848-855Crossref PubMed Scopus (943) Google Scholar).Figure 2Cell of Origin Influences Gene Expression in p3 iPSCsShow full caption(A) Heatmap showing the expression of pluripotency genes in founder cells and p3 iPSCs.(B) Correlation matrix (Spearman’s ρ) of expression data of founder cells, p3 iPSCs, p20 iPSCs, and E14 ESC (n = 2 for all).(C) Correlation matrix (Spearman’s ρ) of H3K27ac ChIP-seq of pro-B, MΦ, MEFs, NSCs, and p3 iPSCs.(D) Heatmap representing H3K27ac enrichment in pro-B, MΦ, MEFs, NSCs, and p3 iPSC. The coverage within 3-kb upstream and downstream of the summit of each H3K27ac peak was calculated and shown for the indicated cell types.(E) Heatmap representing H3K27ac enrichment in pro-B, MΦ, MEFs, NSCs, and p3 iPSCs (similar to D). Genomic regions are the combined ChIP-seq peaks identified in p3 iPSCs.(F) Unsupervised hierarchical clustering of the transcription profiles of p3 iPSCs.(G) k-means clustering of 1,717 differentially expressed genes between the p3 iPSCs. Relative expression change of each differentially expressed gene (as compared with their median expression level across all experiments) is indicated for the founder cells, p3 iPSC and p20 iPSC (n = 2, for every cell type). Clusters and expression difference range (color gradient) are shown.See also Figure S2.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Heatmap showing the expression of pluripotency genes in founder cells and p3 iPSCs. (B) Correlation matrix (Spearman’s ρ) of expression data of founder cells, p3 iPSCs, p20 iPSCs, and E14 ESC (n = 2 for all). (C) Correlation matrix (Spearman’s ρ) of H3K27ac ChIP-seq of pro-B, MΦ, MEFs, NSCs, and p3 iPSCs. (D) Heatmap representing H3K27ac enrichment in pro-B, MΦ, MEFs, NSCs, and p3 iPSC. The coverage within 3-kb upstream and downstream of the summit of each H3K27ac peak was calculated and shown for the indicated cell types. (E) Heatmap representing H3K27ac enrichment in pro-B, MΦ, MEFs, NSCs, and p3 iPSCs (similar to D). Genomic regions are the combined ChIP-seq peaks identified in p3 iPSCs. (F) Unsupervised hierarchical clustering of the transcription profiles of p3 iPSCs. (G) k-means clustering of 1,717 differentially expressed genes between the p3 iPSCs. Relative expression change of each differentially expressed gene (as compared with their median expression level across all experiments) is indicated for the founder cells, p3 iPSC and p20 iPSC (n = 2, for every cell type). Clusters and expression difference range (color gradient) are shown. See also Figure S2. To systematically compare the transcriptomes of the four founder cell types and of their iPSC derivatives, we performed genome-wide expression analysis. Pre-Bs, NSCs, MΦs, and MEFs had highly divergent transcription profiles yet were very similar between biological duplicates (Figure 2B). We identified 13,880 unique genes that were differentially expressed (at an FDR of 0.01) by the four cell types. Reprogramming of the four somatic cells resulted in loss of tissue-specific expression programs and yielded transcriptomes that highly correlated between all iPS lines and strongly corresponded to an ESC-like expression pattern (Figures 2A and 2B). Similarly, active enhancer profiles, as defined by histone H3 lysine 27 acetylation (H3K27ac) were also very different between founder cells (Creyghton et al., 2010Creyghton M.P. Cheng A.W. Welstead G.G. Kooistra T. Carey B.W. Steine E.J. Hanna J. Lodato M.A. Frampton G.M. Sharp P.A. et al.Histone H3K27ac separates active from poised enhancers and predicts developmental state.Proc. Natl. Acad. Sci. USA. 2010; 107: 21931-21936Crossref PubMed Scopus (2493) Google Scholar, Lane et al., 2014Lane A.A. Chapuy B. Lin C.Y. Tivey T. Li H. Townsend E.C. van Bodegom D. Day T.A. Wu S.C. Liu H. et al.Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation.Nat. Genet. 2014; 46: 618-623Crossref PubMed Scopus (97) Google Scholar, Yue et al., 2014Yue F. Cheng Y. Breschi A. Vierstra J. Wu W. Ryba T. Sandstrom R. Ma Z. Davis C. Pope B.D. et al.Mouse ENCODE ConsortiumA comparative encyclopedia of DNA elements in the mouse genome.Nature. 2014; 515: 355-364Crossref PubMed Scopus (1025) Google Scholar) (Figure 2D) but became highly similar after reprogramming in all iPSCs (Figures 2C and 2E), with cell-of-origin-specific sites having very little residual enhancer marks (Figure 2D). Although expression profiles in both p3 and p20 iPSCs were highly correlated, unsupervised hierarchical clustering of the transcription profiles revealed that p3 passage iPSCs derived from the same cell of origin clustered together (Figure 2F). Indeed, 1717 unique genes were differentially expressed (FDR of 0.05) between p3 iPSCs derived from different founders. This indicated that the cell type of origin left a mark on transcription in fully reprogrammed p3 passage iPSCs. In contrast, p20 iPSCs showed clearly reduced gene expression clustering (Figure S2A) and only two genes with reproducibly founder-dependent differential expression (FDR of 0.05). This is consistent with previous reports demonstrating that iPSCs transiently retain cell-type-of-origin differences in gene expression (Kim et al., 2010Kim K. Doi A. Wen B. Ng K. Zhao R. Cahan P. Kim J. Aryee M.J. Ji H. Ehrlich L.I. et al.Epigenetic memory in induced pluripotent stem cells.Nature. 2010; 467: 285-290Crossref PubMed Scopus (1714) Google Scholar, Polo et al., 2010Polo J.M. Liu S. Figueroa M.E. Kulalert W. Eminli S. Tan K.Y. Apostolou E. Stadtfeld M. Li Y. Shioda T. et al.Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells.Nat. Biotechnol. 2010; 28: 848-855Crossref PubMed Scopus (943) Google Scholar). To further understand transcriptional differences and similarities between p3 passage iPSCs derived from different cell types, we performed k-means clustering and identified seven clusters of genes in p3 iPSCs (Figure 2G). To determine whether their differential expression echoed previously established transcription patterns in the cells of origin, we calculated the correlation in expression on a gene-by-gene basis between founders and iPSCs. For p3 iPSCs the expression of genes in most clusters showed little correlation with that of the founders, with the exception of cluster 2 (Figures 2G and S2B) (p < 0.001, Wilcoxon rank sum test). In agreement, Gene Ontology analysis using Webgestalt (Zhang et al., 2005Zhang B. Kirov S. Snoddy J. WebGestalt: an integrated system for exploring gene sets in various biological contexts.Nucleic Acids Res. 2005; 33: W741-W748Crossref PubMed Scopus (1382) Google Scholar) only showed a clear enrichment of functional categories for cluster 2, namely for genes involved in the immune system and collagen (Figure S2C). Consistent with this annotation, genes in this cluster are highly expressed in MΦ-p3 iPSCs and in MEF-p3 iPSCs but not in NSC-derived iPSCs. Vice versa, when we clustered genes according to tissue-specific expression patterns in the founders, we also found no indications for systematic memory of cell-type-specific expression programs in the corresponding p3 and p20 iPSCs (Figure S2D). Furthermore, when we selected tissue-specific genes based on their >4-fold higher expression in one of the founding somatic cell lines compared the other three, we found that none of the genes maintained this difference in transcriptional output in the corresponding iPSCs. Only when we lowered the threshold for differential expression among iPSCs to 1.4-fold, a small number of genes (22) were reproducibly scored across all lineages (16 for MΦ, 5 for pre-B, 1 for MEF, and 0 for NSC) as having a founder-specific expression profile. Collectively, this showed that overall cell-type-specific expression programs were efficiently erased and replaced by ESC-like transcription programs during reprogramming. In addition, reproducible cell-type-of-origin-specific gene expression patterns exist in p3 iPSCs, although only for one gene cluster this is related to a founder-specific gene expression program. The remaining founder-dependent gene expression patterns in p3 iPSCs appear reproducibly acquired during reprogramming, possibly as a consequence of cell-type-specific reprogramming events. To investigate how nuclear organization changes during reprogramming, we used a frequently cutting restriction enzyme (DpnII) to generate genome-wide Hi-C contact maps for each of the four founder cell types and their respective p3 and p20 iPSC derivatives. We prepared Hi-C data from two to three independent clones (with the exception of the NSC founder, from which only one Hi-C library was created), which we combined for each cell type, resulting in Hi-C maps based on 39-72M valid reads (Table S1). We first compared the overall chromosome organization of the different cell types by partitioning the genome into regions of 300kb and plotting all interactions between these regions as a heatmap and a correlation heatmap (Figure 3A; Table S2). As expected, most interactions occurred in cis and at close distance, although many long-range contacts beyond the level of TADs can be observed. Closer inspection of the heatmaps revealed clear differences in genome folding between the different somatic cell types. Reprogramming erased many of these tissue-specific configurations and created a 3D genome that was highly similar between all iPS lines. Previous Hi-C studies have shown that chromosomal regions can be segregated into two main nuclear compartments (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 (4868) Google Scholar). Regions within the same compartment preferentially interacted with each other and were highly enriched for, respectively, active (compartment A) or inactive chromatin (compartment B) (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 (4868) Google Scholar). We found that the distribution of genomic regions between these compartments differed strongly between the somatic lines (Figures 3A–3C), with 28% of the genome located in a different compartment in at least one of the founders. This percentage is not very different from the 36% of the genome that was found to change compartments during in vitro differentiation (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 (944) Google Scholar). Genes tissue specifically residing in the A compartment showed increased expression levels in the corresponding cell type, while those tissue specifically located in the B compartment showed reduced transcriptional output as compared with that in the other tissues (Figure S3). An example of such a gene (Ly6d) with tissue-specific activity and corresponding nuclear location in pre-B cells is shown in Figure 3D. For every cell type of origin, reprogramming efficiently erased the tissue-specific division of genomic regions over the A and B compartments and induced a compartment structure that is very similar to what is found in ESCs (Figures 3A–3C). Already in p3 passage iPSCs, 99.9% of the genome resided in identical compartments, which increased to 99.95% in p20 iPSCs. For example, Sox2 was found to be expressed and located in the active compartment in NSCs, but inactive and located in the B compartment in the other somatic cell types. Reprogramming induced the expression of endogenous Sox2 and relocated the gene to the active compartment in iPSCs derived from pre-B, MΦ, and MEF (Figure 3E). Genes that switched compartments during reprogramming changed their expression levels more often than genes that did not switch compartments (Figure 3F), with genes relocating from B to A showing an overall increase in expression, and vice versa, genes switching from A to B showing an overall reduction in expression in iPSCs. A similar, albeit more subtle, correlation between expression changes and compartment switching was observed before during in vitro differentiation (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 (944) Google Scholar). These data demonstrate that somatic founder cells generally structure their chromosomes very differently, but reprogramming induces these differences to disappear and genomes to adopt an ESC-like higher order structure (Figure 3C). Thus, independently of the somatic founder cell type, reprogramming into iPSCs leads to a convergence of the 3D genomes to an ESC-like topology. The pluripotent genome was previously found to have some unique topological features (de Wit et al., 2013de Wit E. Bouwman B.A. Zhu Y. Klous P. Splinter E. Verstegen M.J. Krijger P.H. Festuccia N. Nora E.P. Welling M. et al.The pluripotent genome in three dimensions is shaped around pluripotency factors.Nature. 2013; 501: 227-231Crossref PubMed Scopus (204) 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 (201) Google Scholar). One such hallmark is the preferential long-range contacts between regions with high-density binding sites of the pluripotency factors NANOG, OCT4, and SOX2 (de Wit et al., 2013de Wit E. Bouwman B.A. Zhu Y. Klous P. Splinter E. Verstegen M.J. Krijger P.H. Festuccia N. Nora E.P. Welling M. et al.The pluripotent genome in three dimensions is shaped around pluripotency fact" @default.
• W2294365510 created "2016-06-24" @default.
• W2294365510 creator A5021842648 @default.
• W2294365510 creator A5023776272 @default.
• W2294365510 creator A5039868300 @default.
• W2294365510 creator A5044038493 @default.
• W2294365510 creator A5068861694 @default.
• W2294365510 creator A5081340727 @default.
• W2294365510 creator A5084506206 @default.
• W2294365510 date "2016-05-01" @default.
• W2294365510 modified "2023-10-10" @default.
• W2294365510 title "Cell-of-Origin-Specific 3D Genome Structure Acquired during Somatic Cell Reprogramming" @default.
• W2294365510 cites W1964487182 @default.
• W2294365510 cites W1971578941 @default.
• W2294365510 cites W1972298775 @default.
• W2294365510 cites W1973062929 @default.
• W2294365510 cites W1980548655 @default.
• W2294365510 cites W1981030303 @default.
• W2294365510 cites W1984340155 @default.
• W2294365510 cites W1986030515 @default.
• W2294365510 cites W1991059160 @default.
• W2294365510 cites W1991543373 @default.
• W2294365510 cites W1995424704 @default.
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• W2294365510 cites W2045269599 @default.
• W2294365510 cites W2056482755 @default.
• W2294365510 cites W2061738297 @default.
• W2294365510 cites W2070021921 @default.
• W2294365510 cites W2070324050 @default.
• W2294365510 cites W2074350232 @default.
• W2294365510 cites W2076799601 @default.
• W2294365510 cites W2080477348 @default.
• W2294365510 cites W2081628067 @default.
• W2294365510 cites W2090037139 @default.
• W2294365510 cites W2091548199 @default.
• W2294365510 cites W2102560467 @default.
• W2294365510 cites W2103428287 @default.
• W2294365510 cites W2125987139 @default.
• W2294365510 cites W2126580353 @default.
• W2294365510 cites W2134146607 @default.
• W2294365510 cites W2143599753 @default.
• W2294365510 cites W2161212572 @default.
• W2294365510 cites W2166649689 @default.
• W2294365510 cites W2169187183 @default.
• W2294365510 cites W2175853567 @default.
• W2294365510 cites W2219020455 @default.
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