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      Multiscale 3D Genome Rewiring during Mouse Neural Development

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Chromosome conformation capture technologies have revealed important insights into genome folding. Yet, how spatial genome architecture is related to gene expression and cell fate remains unclear. We comprehensively mapped 3D chromatin organization during mouse neural differentiation in vitro and in vivo, generating the highest-resolution Hi-C maps available to date. We found that transcription is correlated with chromatin insulation and long-range interactions, but dCas9-mediated activation is insufficient for creating TAD boundaries de novo. Additionally, we discovered long-range contacts between gene bodies of exon-rich, active genes in all cell types. During neural differentiation, contacts between active TADs become less pronounced while inactive TADs interact more strongly. An extensive Polycomb network in stem cells is disrupted, while dynamic interactions between neural transcription factors appear in vivo. Finally, cell type-specific enhancer-promoter contacts are established concomitant to gene expression. This work shows that multiple factors influence the dynamics of chromatin interactions in development.

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          Highlights

          • Ultra-deep Hi-C during mouse neural differentiation, both in vitro and in vivo
          • Transcription is correlated with, but not sufficient for, local chromatin insulation
          • Polycomb network is disrupted, while novel contacts between neural TF sites appear
          • Dynamic contacts among exon-rich gene bodies, enhancer-promoters, and TF sites

          Abstract

          An ultrahigh resolution Hi-C map of mouse neural differentiation yields insights into the multiple factors that influence the dynamics of chromatin interactions during development.

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          Most cited references 23

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          Architectural protein subclasses shape 3D organization of genomes during lineage commitment.

          Understanding the topological configurations of chromatin may reveal valuable insights into how the genome and epigenome act in concert to control cell fate during development. Here, we generate high-resolution architecture maps across seven genomic loci in embryonic stem cells and neural progenitor cells. We observe a hierarchy of 3D interactions that undergo marked reorganization at the submegabase scale during differentiation. Distinct combinations of CCCTC-binding factor (CTCF), Mediator, and cohesin show widespread enrichment in chromatin interactions at different length scales. CTCF/cohesin anchor long-range constitutive interactions that might form the topological basis for invariant subdomains. Conversely, Mediator/cohesin bridge short-range enhancer-promoter interactions within and between larger subdomains. Knockdown of Smc1 or Med12 in embryonic stem cells results in disruption of spatial architecture and downregulation of genes found in cohesin-mediated interactions. We conclude that cell-type-specific chromatin organization occurs at the submegabase scale and that architectural proteins shape the genome in hierarchical length scales. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture.

            Mouse embryonic stem (ES) cells are competent for production of all fetal and adult cell types. However, the utility of ES cells as a developmental model or as a source of defined cell populations for pharmaceutical screening or transplantation is compromised because their differentiation in vitro is poorly controlled. Specification of primary lineages is not understood and consequently differentiation protocols are empirical, yielding variable and heterogeneous outcomes. Here we report that neither multicellular aggregation nor coculture is necessary for ES cells to commit efficiently to a neural fate. In adherent monoculture, elimination of inductive signals for alternative fates is sufficient for ES cells to develop into neural precursors. This process is not a simple default pathway, however, but requires autocrine fibroblast growth factor (FGF). Using flow cytometry quantitation and recording of individual colonies, we establish that the bulk of ES cells undergo neural conversion. The neural precursors can be purified to homogeneity by fluorescence activated cell sorting (FACS) or drug selection. This system provides a platform for defining the molecular machinery of neural commitment and optimizing the efficiency of neuronal and glial cell production from pluripotent mammalian stem cells.
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              Organization of the mitotic chromosome.

              Mitotic chromosomes are among the most recognizable structures in the cell, yet for over a century their internal organization remains largely unsolved. We applied chromosome conformation capture methods, 5C and Hi-C, across the cell cycle and revealed two distinct three-dimensional folding states of the human genome. We show that the highly compartmentalized and cell type-specific organization described previously for nonsynchronous cells is restricted to interphase. In metaphase, we identified a homogenous folding state that is locus-independent, common to all chromosomes, and consistent among cell types, suggesting a general principle of metaphase chromosome organization. Using polymer simulations, we found that metaphase Hi-C data are inconsistent with classic hierarchical models and are instead best described by a linearly organized longitudinally compressed array of consecutive chromatin loops.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                19 October 2017
                19 October 2017
                : 171
                : 3
                : 557-572.e24
                Affiliations
                [1 ]Institute of Human Genetics, UMR 9002 of the CNRS and the Université de Montpellier, 34396 Montpellier, France
                [2 ]Weizmann Institute of Science, Rehovot 76100, Israel
                [3 ]BGI, Shenzhen, 518083 Shenzhen, China
                [4 ]INSERM U1051, Institute for Neurosciences, Hôpital Saint Eloi, Université de Montpellier 2, 34090 Montpellier, France
                Author notes
                []Corresponding author boyan.bonev@ 123456igh.cnrs.fr
                [∗∗ ]Corresponding author giacomo.cavalli@ 123456igh.cnrs.fr
                [5]

                Lead Contact

                Article
                S0092-8674(17)31137-6
                10.1016/j.cell.2017.09.043
                5651218
                29053968
                © 2017 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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