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      The interdependence of gene-regulatory elements and the 3D genome

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          Abstract

          Vermunt et al. discuss the relationship between gene-regulatory elements and nuclear architectural features in transcription.

          Abstract

          Imaging studies, high-resolution chromatin conformation maps, and genome-wide occupancy data of architectural proteins have revealed that genome topology is tightly intertwined with gene expression. Cross-talk between gene-regulatory elements is often organized within insulated neighborhoods, and regulatory cues that induce transcriptional changes can reshape chromatin folding patterns and gene positioning within the nucleus. The cause–consequence relationship of genome architecture and gene expression is intricate, and its molecular mechanisms are under intense investigation. Here, we review the interdependency of transcription and genome organization with emphasis on enhancer–promoter contacts in gene regulation.

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          Nature, nurture, or chance: stochastic gene expression and its consequences.

          Gene expression is a fundamentally stochastic process, with randomness in transcription and translation leading to cell-to-cell variations in mRNA and protein levels. This variation appears in organisms ranging from microbes to metazoans, and its characteristics depend both on the biophysical parameters governing gene expression and on gene network structure. Stochastic gene expression has important consequences for cellular function, being beneficial in some contexts and harmful in others. These situations include the stress response, metabolism, development, the cell cycle, circadian rhythms, and aging.
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            A gene complex controlling segmentation in Drosophila.

            E B Lewis (1978)
            The bithorax gene complex in Drosophila contains a minimum of eight genes that seem to code for substances controlling levels of thoracic and abdominal development. The state of repression of at least four of these genes is controlled by cis-regulatory elements and a separate locus (Polycomb) seems to code for a repressor of the complex. The wild-type and mutant segmentation patterns are consistent with an antero-posterior gradient in repressor concentration along the embryo and a proximo-distal gradient along the chromosome in the affinities for repressor of each gene's cis-regulatory element.
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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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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                Rockefeller University Press
                0021-9525
                1540-8140
                07 January 2019
                : 218
                : 1
                : 12-26
                Affiliations
                [1 ]Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA
                [2 ]Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
                Author notes
                Correspondence to Gerd A. Blobel: blobel@ 123456email.chop.edu
                Author information
                http://orcid.org/0000-0002-3570-1558
                http://orcid.org/0000-0002-0714-9612
                Article
                201809040
                10.1083/jcb.201809040
                6314554
                30442643
                c7c0322e-eef6-4fce-898f-78c6cf2be7c1
                © 2018 Vermunt et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 07 September 2018
                : 29 October 2018
                : 29 October 2018
                Funding
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: RO1DK54937
                Award ID: R01HL119479
                Award ID: R24DK106766
                Award ID: U01HL129998A2017
                Award ID: R37DK058044
                Funded by: Netherlands Organization for Scientific Research
                Award ID: 019.173EN.006
                Categories
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                Review

                Cell biology
                Cell biology

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