For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
350
views
66
references
 Top references
cited by
527
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      32
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: not found

      Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      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.

          Summary

          Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.

          Abstract

          Graphical Abstract

          Highlights

          ► Human bromodomain family characterized with 29 high-resolution crystal structures ► Peptide arrays establish core histone binding preferences of BRD ► Interactions with histone-acetylated lysine sites are quantified ► Flanking posttranslational modifications greatly impact acetylated lysine recognition

          Abstract

          Bromodomains bind acetylated lysines in histones, a key event in the “reading” of epigenetic marks. A foundation for designing inhibitors for this emerging class of drug targets is provided by a systematic biochemical analysis of their binding preferences and a compendium of 29 crystal structures of human bromodomains.

          Related collections

          Most cited references66

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

          A unique chromatin signature uncovers early developmental enhancers in humans.

          Alvaro Rada-Iglesias, Ruchi Bajpai, Tomek Swigut … (2011)
          Cell-fate transitions involve the integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of genomic sequences that control human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs), unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, monomethylation of histone H3 at lysine 4 (H3K4me1), and low nucleosomal density. In addition, elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized hESC enhancers, and are located proximally to genes expressed in hESCs and the epiblast. In contrast, elements of the second class, which we term 'poised enhancers', are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3), and are linked to genes inactive in hESCs and instead are involved in orchestrating early steps in embryogenesis, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of poised enhancers acquires a chromatin signature associated with active enhancers. When assayed in zebrafish embryos, poised enhancers are able to direct cell-type and stage-specific expression characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that early developmental enhancers are epigenetically pre-marked in hESCs and indicate an unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the wealth of new regulatory sequences identified here provides an invaluable resource for studies and isolation of transient, rare cell populations representing early stages of human embryogenesis.
          Article 0 comments Cited 893 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Extraction, purification and analysis of histones.

            David Shechter, Holger Dormann, C. Allis … (2007)
            Histone proteins are the major protein components of chromatin, the physiologically relevant form of the genome (or epigenome) in all eukaryotic cells. Chromatin is the substrate of many biological processes, such as gene regulation and transcription, replication, mitosis and apoptosis. Since histones are extensively post-translationally modified, the identification of these covalent marks on canonical and variant histones is crucial for the understanding of their biological significance. Many different biochemical techniques have been developed to purify and separate histone proteins. Here, we present standard protocols for acid extraction and salt extraction of histones from chromatin; separation of extracted histones by reversed-phase HPLC; analysis of histones and their specific post-translational modification profiles by acid urea (AU) gel electrophoresis and the additional separation of non-canonical histone variants by triton AU(TAU) and 2D TAU electrophoresis; and immunoblotting of isolated histone proteins with modification-specific antibodies.
            Article 0 comments Cited 352 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Structure and ligand of a histone acetyltransferase bromodomain.

              C Dhalluin, J Carlson, L. ZENG … (1999)
              Histone acetylation is important in chromatin remodelling and gene activation. Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are approximately 110-amino-acid modules found in many chromatin-associated proteins. Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so. The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.
              Article 0 comments Cited 327 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): Cell
                Journal ID (iso-abbrev): Cell
                Title: Cell
                Publisher: Cell Press
                ISSN (Print): 0092-8674
                ISSN (Electronic): 1097-4172
                Publication date PMC-release: 30 March 2012
                Publication date (Print): 30 March 2012
                Volume: 149
                Issue: 1
                Pages: 214-231
                Affiliations
                [1 ]Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7LD, UK
                [2 ]Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7LD, UK
                [3 ]Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
                [4 ]Ontario Cancer Institute, Campbell Family Cancer Research Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada
                [5 ]Centre for Systems Biology, Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
                [6 ]Institut für Medizinische Immunologie, Charité-Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany
                [7 ]Department of Molecular Genetics, University of Toronto, 1 Kings College Circle, Toronto, Ontario M5S 1A8, Canada
                [8 ]Department of Biochemistry and Molecular Biology, George Washington University, School of Medicine and Health Sciences, 2300 Eye Street, NW, Suite 530, Washington, DC, 20037, USA
                Author notes
                [∗∗ ]Corresponding author stefan.knapp@ 123456sgc.ox.ac.uk
                Article
                Publisher ID: CELL6135
                DOI: 10.1016/j.cell.2012.02.013
                PMC ID: 3326523
                PubMed ID: 22464331
                SO-VID: 07ea0ad3-9631-4957-ac22-7c00168a90f5
                Copyright © © 2012 ELL & Excerpta Medica.
                License:

                This document may be redistributed and reused, subject to certain conditions.

                History
                Date received : 5 July 2011
                Date revision received : 16 October 2011
                Date accepted : 13 January 2012
                Categories
                Subject: Resource

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

                Comments

                Comment on this article

                scite_

                Similar content32

                See all similar

                Cited by513

                See all cited by

                Most referenced authors2,494

                See all reference authors