The Birth of the 3D Genome during Early Embryonic Development
Authors: Clemens B. Hug, Juan M. Vaquerizas
Journal: Trends in Genetics (2018)

3D chromatin architecture, including topologically associating domains and compartments, are weakened during germline development. Re-establishment of topologically associating domains and compartments occurs during zygotic genome activation. Transcription is associated with domain boundaries, but is neither necessary nor sufficient for their emergence. Several independent mechanisms may have evolved to structure the 3D genome. The 3D structure of chromatin in the nucleus is important for the regulation of gene expression and the correct deployment of developmental programs. The differentiation of germ cells and early embryonic development (when the zygotic genome is activated and transcription is taking place for the first time) are accompanied by dramatic changes in gene expression and the epigenetic landscape. Recent studies used Hi-C to investigate the 3D chromatin organization during these developmental transitions, uncovering remarkable remodeling of the 3D genome. Here, we highlight the changes described so far and discuss some of the implications that these findings have for our understanding of the mechanisms and functionality of 3D chromatin architecture. The 3D structure of chromatin in the nucleus is important for the regulation of gene expression and the correct deployment of developmental programs. The differentiation of germ cells and early embryonic development (when the zygotic genome is activated and transcription is taking place for the first time) are accompanied by dramatic changes in gene expression and the epigenetic landscape. Recent studies used Hi-C to investigate the 3D chromatin organization during these developmental transitions, uncovering remarkable remodeling of the 3D genome. Here, we highlight the changes described so far and discuss some of the implications that these findings have for our understanding of the mechanisms and functionality of 3D chromatin architecture. In recent years, the 3D organization of the genome inside the nucleus and its impact on gene regulation, development, and disease have been studied in increasing levels of detail [1Bonev B. Cavalli G. Organization and function of the 3D genome.Nat. Rev. Genet. 2016; 17: 661-678Crossref PubMed Scopus (533) Google Scholar, 2Long H.K. et al.Ever-changing landscapes: transcriptional enhancers in development and evolution.Cell. 2016; 167: 1170-1187Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar]. As knowledge of the function of genomes and the numerous noncoding elements that make them work has increased, it has become increasingly difficult to conceptualize how all these functional elements work together. It was unclear how different functional units are insulated from each other and, conversely, how regulatory elements that belong together can still interact. Technical advances over the past decade have made it possible to create detailed maps of the way in which chromatin is folded inside the nucleus in 3D space [3Lieberman-Aiden E. et al.Comprehensive mapping of long-range interactions reveals folding principles of the human genome.Science. 2009; 326: 289-293Crossref PubMed Scopus (4899) Google Scholar]. It has now become clear that mapping the 3D genome could explain many aspects of how regulatory sequences and gene expression are connected in such an elegant and parsimonious way. A particular recent focus has been the characterization of the 3D genome in the germline [4Battulin N. et al.Comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach.Genome Biol. 2015; 16: 77Crossref PubMed Scopus (80) Google Scholar, 5Jung Y.H. et al.Chromatin states in mouse sperm correlate with embryonic and adult regulatory landscapes.Cell Rep. 2017; 18: 1366-1382Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 6Flyamer I.M. et al.Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition.Nature. 2017; 25: 82Google Scholar, 7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar, 8Du Z. et al.Allelic reprogramming of 3D chromatin architecture during early mammalian development.Nature. 2017; 547: 232-235Crossref PubMed Scopus (268) Google Scholar] during the first stages of Drosophila [9Hug C.B. et al.Chromatin architecture emerges during zygotic genome activation independent of transcription.Cell. 2017; 169: 216-228Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 10Stadler M.R. et al.Convergence of topological domain boundaries, insulators, and polytene interbands revealed by high-resolution mapping of chromatin contacts in the early Drosophila melanogaster embryo.eLife. 2017; 6e29550Crossref PubMed Scopus (58) Google Scholar] and mouse embryo development [7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar, 8Du Z. et al.Allelic reprogramming of 3D chromatin architecture during early mammalian development.Nature. 2017; 547: 232-235Crossref PubMed Scopus (268) Google Scholar]. The epigenetic landscape undergoes extensive remodeling during germline development and during the transition from a totipotent to a lineage-committed state [11Hammoud S.S. et al.Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis.Cell Stem Cell. 2014; 15: 239-253Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 12Xu Q. Xie W. Epigenome in early mammalian development: inheritance, reprogramming and establishment.Trends Cell Biol. 2018; 28: 237-253Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. Therefore, these stages are uniquely suitable for studying the interdependencies of chromatin architecture, transcription factor binding, and gene expression. Here, we summarize recent findings relating to the 3D architecture of chromatin in the germline as well as during early embryonic development, and discuss the implications of these findings for our understanding of the 3D genome. Chromatin in the interphase nucleus is organized in a multilayered fashion (Figure 1): It locally assembles into topologically associating domains (TADs; see Glossary) and globally alternates between two different compartments (active and inactive), where it is in contact with other domains of the same kind over very long distances [3Lieberman-Aiden E. et al.Comprehensive mapping of long-range interactions reveals folding principles of the human genome.Science. 2009; 326: 289-293Crossref PubMed Scopus (4899) Google Scholar, 13Dixon J.R. et al.Topological domains in mammalian genomes identified by analysis of chromatin interactions.Nature. 2012; 485: 376-380Crossref PubMed Scopus (3983) Google Scholar, 14Nora E.P. et al.Spatial partitioning of the regulatory landscape of the X-inactivation centre.Nature. 2012; 485: 381-385Crossref PubMed Scopus (1825) Google Scholar]. The regulatory impact and functional relevance of TADs are currently under investigation. There is evidence that TADs serve an organizational purpose, by separating the genome into modular units that are functionally insulated from each other [13Dixon J.R. et al.Topological domains in mammalian genomes identified by analysis of chromatin interactions.Nature. 2012; 485: 376-380Crossref PubMed Scopus (3983) Google Scholar, 15Rao S.S.P. 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 (3630) Google Scholar, 16Lupiáñez D.G. et al.Breaking TADs: how alterations of chromatin domains result in disease.Trends Genet. 2016; 32: 225-237Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar]. Evidence for this model comes from the observation that regulatory elements, such as enhancers, are unable to influence gene expression outside their own TAD environment, and the frequent coregulation of genes within the same TAD across tissues [14Nora E.P. et al.Spatial partitioning of the regulatory landscape of the X-inactivation centre.Nature. 2012; 485: 381-385Crossref PubMed Scopus (1825) Google Scholar, 15Rao S.S.P. 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 (3630) Google Scholar]. The functional role of compartments is less clear. They represent clusters in the nucleus, where TADs of the same class physically cluster together in space [17Wang S. et al.Spatial organization of chromatin domains and compartments in single chromosomes.Science. 2016; 353: 598-602Crossref PubMed Scopus (325) Google Scholar]. Usually, two compartment types are distinguished: A-compartments are transcriptionally active, gene rich, and DNAse I accessible, whereas B-compartments are gene poor, transcriptionally silent, inaccessible, and partly marked by H3K27me3 [3Lieberman-Aiden E. et al.Comprehensive mapping of long-range interactions reveals folding principles of the human genome.Science. 2009; 326: 289-293Crossref PubMed Scopus (4899) Google Scholar, 15Rao S.S.P. 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 (3630) Google Scholar]. TAD and compartment structure are independent and probably mediated by separate mechanisms (reviewed in [18Nuebler J. et al.Chromatin organization by an interplay of loop extrusion and compartmental segregation.Proc. Natl. Acad. 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This canonical 3D chromatin structure, as described here, undergoes regular remodeling during different processes, such as cell cycle, differentiation, and development (reviewed in [16Lupiáñez D.G. et al.Breaking TADs: how alterations of chromatin domains result in disease.Trends Genet. 2016; 32: 225-237Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 24Merkenschlager M. Nora E.P. CTCF and cohesin in genome folding and transcriptional gene regulation.Annu. Rev. Genomics Hum. Genet. 2016; 17: 17-43Crossref PubMed Scopus (288) Google Scholar]). Several studies have investigated the interplay between 3D chromatin architecture, mitosis, and cell differentiation. Until recently, however, it was unclear whether similar global restructuring events occur during differentiation of the germline lineage or after fertilization in the zygote, when embryonic development begins. Chromatin of mammalian sperm is remarkably different than that found in typical somatic cells. The nuclear volume of mouse sperm compared with liver cells is reduced by approximately 40-fold [25Ward W.S. Coffey D.S. DNA packaging and organization in mammalian spermatozoa: comparison with somatic cells.Biol. Reprod. 1991; 44: 569-574Crossref PubMed Scopus (540) Google Scholar] and previous observations showed that between 85% and 98% of chromatin is wrapped around protamines instead of nucleosomes [5Jung Y.H. et al.Chromatin states in mouse sperm correlate with embryonic and adult regulatory landscapes.Cell Rep. 2017; 18: 1366-1382Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]. Mature sperm cells are haploid and transcriptionally inactive, even though some promoters appear to retain a nucleosome-free region and binding of some core transcription factors [26Carone B.R. et al.High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm.Dev. Cell. 2014; 30: 11-22Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]. Despite these differences, the 3D chromatin structure of mouse sperm, as determined by Hi-C, is remarkably similar to that of somatic cells [5Jung Y.H. et al.Chromatin states in mouse sperm correlate with embryonic and adult regulatory landscapes.Cell Rep. 2017; 18: 1366-1382Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 4Battulin N. et al.Comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach.Genome Biol. 2015; 16: 77Crossref PubMed Scopus (80) Google Scholar, 7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar], with TADs and loops conserved between tissues. One of the few noticeable differences is a distinctive enrichment of contacts at distances above 10 Mb [5Jung Y.H. et al.Chromatin states in mouse sperm correlate with embryonic and adult regulatory landscapes.Cell Rep. 2017; 18: 1366-1382Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 4Battulin N. et al.Comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach.Genome Biol. 2015; 16: 77Crossref PubMed Scopus (80) Google Scholar, 7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar, 8Du Z. et al.Allelic reprogramming of 3D chromatin architecture during early mammalian development.Nature. 2017; 547: 232-235Crossref PubMed Scopus (268) Google Scholar] and an approximately twofold increase in the frequency of interchromosomal contacts [4Battulin N. et al.Comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach.Genome Biol. 2015; 16: 77Crossref PubMed Scopus (80) Google Scholar], which are probably due to the higher nuclear density of the sperm cell. The nuclear architecture of mouse oocytes is less clear-cut and subject to great variation during their development [27De La Fuente R. Chromatin modifications in the germinal vesicle (GV) of mammalian oocytes.Dev. Biol. 2006; 292: 1-12Crossref PubMed Scopus (195) Google Scholar]. One study examined the 3D chromatin architecture of mouse germinal vesicle stage oocytes using single-cell Hi-C [6Flyamer I.M. et al.Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition.Nature. 2017; 25: 82Google Scholar]. They found evidence of a global interaction shift during the transition from transcriptionally active immature oocytes to transcriptionally silent mature oocytes. Using aggregate loop and aggregate TAD analysis, the authors were able to show that the intensity of TADs and loops significantly decreased during oocyte maturation. Two other studies examined mouse oocytes at a later stage during meiosis II using population Hi-C and found them to be almost completely devoid of TADs and loops [7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar, 8Du Z. et al.Allelic reprogramming of 3D chromatin architecture during early mammalian development.Nature. 2017; 547: 232-235Crossref PubMed Scopus (268) Google Scholar]. Together, these results show that 3D chromatin organization decreases progressively during oocyte development and suggest that the formation of compacted chromatin during the metaphase of meiosis II affects the higher order structure, as happens during mitosis (see later). However, technical differences in the experimental methods and analysis techniques between the three oocyte studies preclude direct quantitative comparison of their results across oocyte development. In conclusion, these results demonstrate that the mature germline tissues (sperm and oocytes) have drastically divergent 3D genome structures. While sperm cells retain most of the 3D features of somatic cells, in oocytes, the structural transition during their maturation is dramatic and could be of interest in the future to study the mechanisms behind TAD and loop formation. During fertilization, the two gametes fuse to produce a zygote. The developmental stage following fertilization is of particular interest because it is accompanied by a dramatic shift in gene regulation. In all animals and plants, the zygote and early embryo are transcriptionally inactive for a species-dependent time and rely solely on gene products deposited in the oocyte by the mother for their development (Box 1) [28Tadros W. Lipshitz H.D. The maternal-to-zygotic transition: a play in two acts.Development. 2009; 136: 3033-3042Crossref PubMed Scopus (771) Google Scholar]. In a dramatic turn of events, the zygotic genome is activated, and transcription starts for the first time. The zygotic genome activation (ZGA) is characterized by widespread recruitment of RNA polymerase II (RNA Pol II) [29Blythe S.A. Wieschaus E.F. Zygotic genome activation triggers the DNA replication checkpoint at the midblastula transition.Cell. 2015; 160: 1169-1181Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 30Zeitlinger J. et al.RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo.Nat. 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Establishment and maintenance of heritable chromatin structure during early Drosophila embryogenesis.eLife. 2016; 5e20148Crossref PubMed Scopus (86) Google Scholar, 33Lu F. et al.Establishing chromatin regulatory landscape during mouse preimplantation development.Cell. 2016; 165: 1375-1388Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 34Wu J. et al.The landscape of accessible chromatin in mammalian preimplantation embryos.Nature. 2016; 534: 652-657Crossref PubMed Scopus (369) Google Scholar, 35Gao L. et al.Chromatin accessibility landscape in human early embryos and its association with evolution.Cell. 2018; 173 (248–259.e15)Abstract Full Text Full Text PDF Scopus (105) Google Scholar], and changes in covalent histone modifications [36Li X.-Y. et al.Establishment of regions of genomic activity during the Drosophila maternal to zygotic transition.eLife. 2014; 3e03737Crossref Scopus (120) Google Scholar, 37Dahl J.A. et al.Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition.Nature. 2016; 537: 548-552Crossref PubMed Scopus (336) Google Scholar, 38Zhang B. et al.Allelic reprogramming of the histone modification H3K4me3 in early mammalian development.Nature. 2016; 537: 553-557Crossref PubMed Scopus (367) Google Scholar, 39Liu X. et al.Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos.Nature. 2016; 537: 558-562Crossref PubMed Scopus (379) Google Scholar]. These developments in the zygotic epigenome have recently been reviewed elsewhere [12Xu Q. Xie W. Epigenome in early mammalian development: inheritance, reprogramming and establishment.Trends Cell Biol. 2018; 28: 237-253Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar].Box 1The Maternal-to-Zygotic TransitionThe maternal-to-zygotic transition (MZT) is a developmental process that occurs early during development in all animals and plants. It marks the end of maternal control and the beginning of the independent development of the embryo. There are several excellent reviews describing the processes surrounding MZT in detail elsewhere [12Xu Q. Xie W. Epigenome in early mammalian development: inheritance, reprogramming and establishment.Trends Cell Biol. 2018; 28: 237-253Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 28Tadros W. Lipshitz H.D. The maternal-to-zygotic transition: a play in two acts.Development. 2009; 136: 3033-3042Crossref PubMed Scopus (771) Google Scholar]. Here, we give a short overview.Two separate processes occur more or less concurrently: (i) degradation of maternal gene products; and (ii) activation of transcription from the zygotic genome. During oogenesis, a substantial amount of transcripts and proteins is deposited into the developing oocyte. In total, between 40% (mouse) and 65% (Drosophila) of the protein-coding transcriptome is provided maternally in the zygote. Approximately one third of all maternal RNA undergo active degradation during MZT, likely to remove gene products that are unnecessary or detrimental for further embryonic development.After fertilization, the genome is inactive and generally does not engage in transcription for a species-specific amount of time. Early development is wholly controlled by maternal factors deposited in the oocyte. Zygotic genome activation (ZGA) is the process by which transcription is activated during development. Roughly, this happens in two stages: first, a small subset of genes is activated at early stages in the minor wave of ZGA; second, large-scale activation of genes occurs later during development, resulting in the major wave of ZGA. The transition between these two waves occurs gradually. In Drosophila, the two waves occur at nuclear cycle 8 (minor wave) and 14 (mayor wave), although ZGA is preceded by a massive recruitment of RNA Pol II to promoters in nuclear cycle 13. At most loci, transcription is stalled until nuclear cycle 14, when elongation by the previously recruited RNA polymerase II (RNA Pol II) starts [29Blythe S.A. Wieschaus E.F. Zygotic genome activation triggers the DNA replication checkpoint at the midblastula transition.Cell. 2015; 160: 1169-1181Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. In mice, the minor wave of ZGA occurs in the zygote, while the major wave occurs during the two-cell stage [28Tadros W. Lipshitz H.D. The maternal-to-zygotic transition: a play in two acts.Development. 2009; 136: 3033-3042Crossref PubMed Scopus (771) Google Scholar]. The maternal-to-zygotic transition (MZT) is a developmental process that occurs early during development in all animals and plants. It marks the end of maternal control and the beginning of the independent development of the embryo. There are several excellent reviews describing the processes surrounding MZT in detail elsewhere [12Xu Q. Xie W. Epigenome in early mammalian development: inheritance, reprogramming and establishment.Trends Cell Biol. 2018; 28: 237-253Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 28Tadros W. Lipshitz H.D. The maternal-to-zygotic transition: a play in two acts.Development. 2009; 136: 3033-3042Crossref PubMed Scopus (771) Google Scholar]. Here, we give a short overview. Two separate processes occur more or less concurrently: (i) degradation of maternal gene products; and (ii) activation of transcription from the zygotic genome. During oogenesis, a substantial amount of transcripts and proteins is deposited into the developing oocyte. In total, between 40% (mouse) and 65% (Drosophila) of the protein-coding transcriptome is provided maternally in the zygote. Approximately one third of all maternal RNA undergo active degradation during MZT, likely to remove gene products that are unnecessary or detrimental for further embryonic development. After fertilization, the genome is inactive and generally does not engage in transcription for a species-specific amount of time. Early development is wholly controlled by maternal factors deposited in the oocyte. Zygotic genome activation (ZGA) is the process by which transcription is activated during development. Roughly, this happens in two stages: first, a small subset of genes is activated at early stages in the minor wave of ZGA; second, large-scale activation of genes occurs later during development, resulting in the major wave of ZGA. The transition between these two waves occurs gradually. In Drosophila, the two waves occur at nuclear cycle 8 (minor wave) and 14 (mayor wave), although ZGA is preceded by a massive recruitment of RNA Pol II to promoters in nuclear cycle 13. At most loci, transcription is stalled until nuclear cycle 14, when elongation by the previously recruited RNA polymerase II (RNA Pol II) starts [29Blythe S.A. Wieschaus E.F. Zygotic genome activation triggers the DNA replication checkpoint at the midblastula transition.Cell. 2015; 160: 1169-1181Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. In mice, the minor wave of ZGA occurs in the zygote, while the major wave occurs during the two-cell stage [28Tadros W. Lipshitz H.D. The maternal-to-zygotic transition: a play in two acts.Development. 2009; 136: 3033-3042Crossref PubMed Scopus (771) Google Scholar]. Given this global shift in the epigenetic state of chromatin and the widespread activation of transcription, it is interesting to look at the 3D chromatin architecture, which is thought to reflect the differentiation status and transcriptional state of cells. Here, we review multiple studies that have examined the 3D architecture of chromatin during the transition from an inactive to active genome [6Flyamer I.M. et al.Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition.Nature. 2017; 25: 82Google Scholar, 7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar, 8Du Z. et al.Allelic reprogramming of 3D chromatin architecture during early mammalian development.Nature. 2017; 547: 232-235Crossref PubMed Scopus (268) Google Scholar, 9Hug C.B. et al.Chromatin architecture emerges during zygotic genome activation independent of transcription.Cell. 2017; 169: 216-228Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 40Gassler J. et al.A mechanism of cohesin-dependent loop extrusion organizes zygotic genome architecture.EMBO J. 2017; 36: 3600-3618Crossref PubMed Scopus (184) Google Scholar]. Taken together, these studies show a drastic reorganization of genome-wide 3D chromatin structure during ZGA that occurs concomitantly with the establishment of zygotic transcription. The interphase 3D chromatin architecture before ZGA is markedly different than that after transcription has been established. Population Hi-C studies in mice and Drosophila found that the short-range TAD structure, long-distance compartmentalization, and focal DNA loops are largely absent before ZGA, which occurs around the late two-cell stage in mouse and nuclear cycle 14 in Drosophila embryos (Figure 2) [7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar, 8Du Z. et al.Allelic reprogramming of 3D chromatin architecture during early mammalian development.Nature. 2017; 547: 232-235Crossref PubMed Scopus (268) Google Scholar, 9Hug C.B. et al.Chromatin architecture emerges during zygotic genome activation independent of transcription.Cell. 2017; 169: 216-228Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar]. The unstructured state that occurs before ZGA is distinct from that observed in mitotic chromosomes, which is characterized by higher levels of long-distance contacts [9Hug C.B. et al.Chromatin architecture emerges during zygotic genome activation independent of transcription.Cell. 2017; 169: 216-228Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 41Naumova N. et al.Organization of the mitotic chromosome.Science. 2013; 342: 948-953Crossref PubMed Scopus (599) Google Scholar]. Pre-ZGA chromatin contacts in the mouse zygote and Drosophila nuclear cycle 12 appear to be stochastic and relatively decondensed [6Flyamer I.M. et al.Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition.Nature. 2017; 25: 82Google Scholar, 7Ke Y. et al.3D chromatin structures of mature gametes and structural reprogramming during mammalian embryogenesis.Cell. 2017; 170 (367–381.e20)Abstract Full Text Full Text PDF Scopus (268) Google Scholar, 8Du Z. et al.Allelic reprogramming of 3D chromatin architecture during early mammalian development.Nature. 2017; 547: 232-235Crossref PubMed Scopus (268) Google Scholar, 9Hug C.B. et al.Chromatin architecture emerges during zygotic genome activation independent of transcription.Cell. 2017; 169: 216-228Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar]. At this developmental stage, chromatin is characterized by uniform contact probabilities across the entire genome with little local variation, suggesting an unpredictable, unordered chromatin structure without locus-specific contac