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      Dissecting super-enhancer hierarchy based on chromatin interactions

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          Abstract

          Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, here we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants. Genetic ablation of hub enhancers results in profound defects in gene activation and local chromatin landscape. As such, hub enhancers are the major constituents responsible for SE functional and structural organization.

          Abstract

          Super-enhancers (SEs) are important regulatory elements for gene expression, but their intrinsic properties remain poorly understood. Here the authors analyse Hi-C and ChIP-seq data and find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers.

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          BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis

          Matthew Canver, Elenoe Smith, Falak Sher … (2015)
          Summary Enhancers, critical determinants of cellular identity, are commonly identified by correlative chromatin marks and gain-of-function potential, though only loss-of-function studies can demonstrate their requirement in the native genomic context. Previously we identified an erythroid enhancer of BCL11A, subject to common genetic variation associated with fetal hemoglobin (HbF) level, whose mouse ortholog is necessary for erythroid BCL11A expression. Here we develop pooled CRISPR-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse enhancers. This approach reveals critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear primate-specific. Through editing of primary human progenitors and mouse transgenesis, we validate the BCL11A erythroid enhancer as a target for HbF reinduction. The detailed enhancer map will inform therapeutic genome editing. The screening approach described here is generally applicable to functional interrogation of noncoding genomic elements.
          Article 0 comments Cited 326 times – based on 0 reviews     Review now
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            Systematic mapping of functional enhancer-promoter connections with CRISPR interference.

            Charles Fulco, Mathias Munschauer, Rockwell Anyoha … (2016)
            Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding elements remain unknown. We present a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. We assess >1 megabase of sequence in the vicinity of two essential transcription factors, MYC and GATA1, and identify nine distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the seven enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. This CRISPRi-based approach can be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.
            Article 0 comments Cited 268 times – based on 0 reviews     Review now
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              CEAS: cis-regulatory element annotation system.

              Hyunjin Shin, Tao Liu, Arjun K Manrai … (2009)
              We present a tool designed to characterize genome-wide protein-DNA interaction patterns from ChIP-chip and ChIP-Seq data. This stand-alone extension of our web application CEAS (cis-regulatory element annotation system) provides summary statistics on ChIP enrichment in important genomic regions such as individual chromosomes, promoters, gene bodies or exons, and infers the genes most likely to be regulated by the binding factor under study. CEAS also enables biologists to visualize the average ChIP enrichment signals over specific genomic regions, particularly allowing observation of continuous and broad ChIP enrichment that might be too subtle to detect from ChIP peaks alone. The CEAS Python package is publicly available at http://liulab.dfci.harvard.edu/CEAS.
              Article 0 comments Cited 236 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jian Xu: jian.xu@utsouthwestern.edu
                Guo-Cheng Yuan:
                ORCID: http://orcid.org/0000-0002-2283-4714
                gcyuan@jimmy.harvard.edu
                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 5 March 2018
                Publication date PMC-release: 5 March 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 943
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Biostatistics and Computational Biology, , Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, ; Boston, MA 02215 USA
                [2 ]ISNI 000000041936754X, GRID grid.38142.3c, Division of Hematology/Oncology, Boston Childrens Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, , Harvard Medical School, ; Boston, MA 02215 USA
                [3 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Department of Pediatrics, Childrens Medical Center Research Institute, , University of Texas Southwestern Medical Center, ; Dallas, TX 75390 USA
                [4 ]ISNI 0000 0001 2167 1581, GRID grid.413575.1, Howard Hughes Medical Institute, ; Boston, MA 02215 USA
                Author information
                http://orcid.org/0000-0002-2283-4714
                Article
                Publisher ID: 3279
                DOI: 10.1038/s41467-018-03279-9
                PMC ID: 5838163
                PubMed ID: 29507293
                SO-VID: d70c3f2c-6be1-4f72-b9f5-9a4c790513b6
                Copyright © © The Author(s) 2018
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 28 July 2017
                Date accepted : 1 February 2018
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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