4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      How subtle changes in 3D structure can create large changes in transcription

      research-article

      Read this article at

      Bookmark
          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.

          Abstract

          Animal genomes are organized into topologically associated domains (TADs). TADs are thought to contribute to gene regulation by facilitating enhancer-promoter (E-P) contacts within a TAD and preventing these contacts across TAD borders. However, the absolute difference in contact frequency across TAD boundaries is usually less than 2-fold, even though disruptions of TAD borders can change gene expression by 10-fold. Existing models fail to explain this hypersensitive response. Here, we propose a futile cycle model of enhancer-mediated regulation that can exhibit hypersensitivity through bistability and hysteresis. Consistent with recent experiments, this regulation does not exhibit strong correlation between E-P contact and promoter activity, even though regulation occurs through contact. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of E-P biochemical specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile apparently contradictory results from recent global TAD disruption with local TAD boundary deletion experiments. Together, these analyses advance our understanding of cis-regulatory contacts in controlling gene expression and suggest new experimental directions.

          Related collections

          Most cited references92

          • Record: found
          • Abstract: found
          • Article: not found

          A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.

          We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ∼10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs "facing" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats. Copyright © 2014 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions

            The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories (CT), and numerous models have been proposed for how chromosomes fold within CTs 1 . These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid revolutions in the study of 3D genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide 2 . In the present study, we investigated the 3D organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term “topological domains”, as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, suggesting that topological domains are an inherent property of mammalian genomes. Lastly, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, tRNAs, and SINE retrotransposons, suggesting that these factors may play a role in establishing the topological domain structure of the genome.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Coactivator condensation at super-enhancers links phase separation and gene control

              Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here, we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets and MED1-IDR droplets can compartmentalize and concentrate transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in control of key cell identity genes.
                Bookmark

                Author and article information

                Contributors
                Role: Senior Editor
                Role: Reviewing Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                09 July 2021
                2021
                : 10
                : e64320
                Affiliations
                [1 ] Program in Biophysics, Stanford University Stanford United States
                [2 ] Department of Developmental Biology, Stanford University Stanford United States
                Weizmann Institute of Science Israel
                University of Massachusetts Medical School United States
                University of Massachusetts Medical School United States
                Gladstone Institutes United States
                University of Massachusetts Medical School United States
                Author information
                https://orcid.org/0000-0001-8072-9341
                https://orcid.org/0000-0003-4927-5227
                https://orcid.org/0000-0002-3554-5196
                Article
                64320
                10.7554/eLife.64320
                8352591
                34240703
                280393ff-a7ee-4122-9374-7b608414b6bf
                © 2021, Xiao et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 25 October 2020
                : 25 June 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: U01 DK127419
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, NIH;
                Award ID: DGM132935A
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100005492, Stanford University;
                Award ID: GM008294
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100005492, Stanford University;
                Award ID: The Walter V. and Idun Berry Postdoctoral Fellowship Program
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
                Award ID: CASI
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Chromosomes and Gene Expression
                Computational and Systems Biology
                Custom metadata
                Promoter futile cycles can explain how subtle differences in genome folding sometimes generate large difference in gene expression.

                Life sciences
                stochastic modeling,transcription,tad,3d genome,d. melanogaster,human,mouse
                Life sciences
                stochastic modeling, transcription, tad, 3d genome, d. melanogaster, human, mouse

                Comments

                Comment on this article