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      The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances

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          Summary

          Gene expression often requires interaction between promoters and distant enhancers, which occur within the context of highly organized topologically associating domains (TADs). Using a series of engineered chromosomal rearrangements at the Shh locus, we carried out an extensive fine-scale characterization of the factors that govern the long-range regulatory interactions controlling Shh expression. We show that Shh enhancers act pervasively, yet not uniformly, throughout the TAD. Importantly, changing intra-TAD distances had no impact on Shh expression. In contrast, inversions disrupting the TAD altered global folding of the region and prevented regulatory contacts in a distance-dependent manner. Our data indicate that the Shh TAD promotes distance-independent contacts between distant regions that would otherwise interact only sporadically, enabling functional communication between them. In large genomes where genomic distances per se can limit regulatory interactions, this function of TADs could be as essential for gene expression as the formation of insulated neighborhoods.

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          Highlights

          • Potential for responsiveness to Shh enhancers correlates with contact frequency

          • Changing distances within Shh TAD has little effect on Shh expression

          • Inversions bridging the Shh TAD boundaries disrupt folding and regulatory contacts

          • Decreasing genomic distance can rescue disrupted long-range regulatory interactions

          Abstract

          Using systematic genomic rearrangements at the Shh locus, Symmons et al. demonstrate that the topologically associating domain overlapping the locus acts as a functional regulatory mold by promoting contacts between elements that would otherwise be too rare to yield a functional outcome due to the dampening effects of large genomic distances.

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          Most cited references48

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          A map of the cis-regulatory sequences in the mouse genome.

          The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 × 10(9) bases of the mouse genome possess a high degree of conservation with the human genome, so a thorough annotation of the mouse genome will be of significant value to understanding the function of the human genome. So far, most of the functional sequences in the mouse genome have yet to be found, and the cis-regulatory sequences in particular are still poorly annotated. Comparative genomics has been a powerful tool for the discovery of these sequences, but on its own it cannot resolve their temporal and spatial functions. Recently, ChIP-Seq has been developed to identify cis-regulatory elements in the genomes of several organisms including humans, Drosophila melanogaster and Caenorhabditis elegans. Here we apply the same experimental approach to a diverse set of 19 tissues and cell types in the mouse to produce a map of nearly 300,000 murine cis-regulatory sequences. The annotated sequences add up to 11% of the mouse genome, and include more than 70% of conserved non-coding sequences. We define tissue-specific enhancers and identify potential transcription factors regulating gene expression in each tissue or cell type. Finally, we show that much of the mouse genome is organized into domains of coordinately regulated enhancers and promoters. Our results provide a resource for the annotation of functional elements in the mammalian genome and for the study of mechanisms regulating tissue-specific gene expression.
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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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              Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor.

              Chromatin loops juxtapose distal enhancers with active promoters, but their molecular architecture and relationship with transcription remain unclear. In erythroid cells, the locus control region (LCR) and β-globin promoter form a chromatin loop that requires transcription factor GATA1 and the associated molecule Ldb1. We employed artificial zinc fingers (ZF) to tether Ldb1 to the β-globin promoter in GATA1 null erythroblasts, in which the β-globin locus is relaxed and inactive. Remarkably, targeting Ldb1 or only its self-association domain to the β-globin promoter substantially activated β-globin transcription in the absence of GATA1. Promoter-tethered Ldb1 interacted with endogenous Ldb1 complexes at the LCR to form a chromatin loop, causing recruitment and phosphorylation of RNA polymerase II. ZF-Ldb1 proteins were inactive at alleles lacking the LCR, demonstrating that their activities depend on long-range interactions. Our findings establish Ldb1 as a critical effector of GATA1-mediated loop formation and indicate that chromatin looping causally underlies gene regulation. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Dev Cell
                Dev. Cell
                Developmental Cell
                Cell Press
                1534-5807
                1878-1551
                05 December 2016
                05 December 2016
                : 39
                : 5
                : 529-543
                Affiliations
                [1 ]Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany
                [2 ]Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany
                Author notes
                []Corresponding author francois.spitz@ 123456pasteur.fr
                [3]

                Present address: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA

                [4]

                Present address: Department of Chromatin Regulation, Max-Planck-Institut für Immunbiologie, 79108 Freiburg, Germany

                [5]

                Present address: Department of Developmental and Stem Cell Biology, Institut Pasteur, 75015 Paris, France

                [6]

                Lead Contact

                Article
                S1534-5807(16)30753-5
                10.1016/j.devcel.2016.10.015
                5142843
                27867070
                62039407-8c54-49b0-934a-ed28557057a1
                © 2016 The Authors

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

                History
                : 19 May 2016
                : 1 August 2016
                : 18 October 2016
                Categories
                Article

                Developmental biology
                gene expression,long-distance enhancers,chromatin conformation,shh,topological domains

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