Intact Nucleosomal Context Enables Chromodomain Reader
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JB Review Biochemical and Structural Properties of Heterochromatin Protein 1: Understanding Its Role in Chromatin Assembly
J. Biochem. 2014;1Journal10 doi:10.1093/jb/mvu032 of Biochemistry Advance Access published June 4, 2014 JB Review Biochemical and structural properties of heterochromatin protein 1: understanding its role in chromatin assembly Received March 20, 2014; accepted April 9, 2014; published online May 13, 2014 Gohei Nishibuchi and Jun-ichi Nakayama* homologues and isoforms have been identified in eu- karyotic organisms, ranging from fission yeast to Graduate School of Natural Sciences, Nagoya City University, mammals, flies, and nematodes (69). In mammals, Nagoya 467-8501, Japan the three HP1 isoforms HP1a, HP1b and HP1g *Jun-ichi Nakayama, Graduate School of Natural Sciences, Nagoya (Fig. 1A) have different localization patterns within City University, 1 Yamanohata, Mizuho-cho, Mizuho-ku, Nagoya cells (11, 12). Mice deficient for each HP1 isoform ex- 467-8501, Japan. Tel: þ81-52-872-5838, Fax: þ81-52-872-5866, email: [email protected] hibit different phenotypes (1315), indicating that the isoforms have distinct functions in forming higher- Heterochromatin protein 1 (HP1) is an evolutionarily order chromatin structures. conserved chromosomal protein that binds lysine HP1-family proteins share a basic structure consist- Downloaded from 9-methylated histone H3 (H3K9me), a hallmark of het- ing of an amino-terminal chromodomain (CD) and a erochromatin, and plays a crucial role in forming carboxyl-terminal chromo shadow domain (CSD) higher-order chromatin structures. HP1 has an N-ter- linked by an unstructured hinge region (16). The CD minal chromodomain and a C-terminal chromo shadow functions as a binding module that targets lysine domain, linked by an unstructured hinge region. -
Functional Roles of Bromodomain Proteins in Cancer
cancers Review Functional Roles of Bromodomain Proteins in Cancer Samuel P. Boyson 1,2, Cong Gao 3, Kathleen Quinn 2,3, Joseph Boyd 3, Hana Paculova 3 , Seth Frietze 3,4,* and Karen C. Glass 1,2,4,* 1 Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA; [email protected] 2 Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; [email protected] 3 Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; [email protected] (C.G.); [email protected] (J.B.); [email protected] (H.P.) 4 University of Vermont Cancer Center, Burlington, VT 05405, USA * Correspondence: [email protected] (S.F.); [email protected] (K.C.G.) Simple Summary: This review provides an in depth analysis of the role of bromodomain-containing proteins in cancer development. As readers of acetylated lysine on nucleosomal histones, bromod- omain proteins are poised to activate gene expression, and often promote cancer progression. We examined changes in gene expression patterns that are observed in bromodomain-containing proteins and associated with specific cancer types. We also mapped the protein–protein interaction network for the human bromodomain-containing proteins, discuss the cellular roles of these epigenetic regu- lators as part of nine different functional groups, and identify bromodomain-specific mechanisms in cancer development. Lastly, we summarize emerging strategies to target bromodomain proteins in cancer therapy, including those that may be essential for overcoming resistance. Overall, this review provides a timely discussion of the different mechanisms of bromodomain-containing pro- Citation: Boyson, S.P.; Gao, C.; teins in cancer, and an updated assessment of their utility as a therapeutic target for a variety of Quinn, K.; Boyd, J.; Paculova, H.; cancer subtypes. -
Dual Recognition of H3k4me3 and H3k27me3 by a Plant Histone Reader SHL
ARTICLE DOI: 10.1038/s41467-018-04836-y OPEN Dual recognition of H3K4me3 and H3K27me3 by a plant histone reader SHL Shuiming Qian1,2, Xinchen Lv3,4, Ray N. Scheid1,2,LiLu1,2, Zhenlin Yang3,4, Wei Chen3, Rui Liu3, Melissa D. Boersma2, John M. Denu2,5,6, Xuehua Zhong 1,2 & Jiamu Du 3 The ability of a cell to dynamically switch its chromatin between different functional states constitutes a key mechanism regulating gene expression. Histone mark “readers” display 1234567890():,; distinct binding specificity to different histone modifications and play critical roles in reg- ulating chromatin states. Here, we show a plant-specific histone reader SHORT LIFE (SHL) capable of recognizing both H3K27me3 and H3K4me3 via its bromo-adjacent homology (BAH) and plant homeodomain (PHD) domains, respectively. Detailed biochemical and structural studies suggest a binding mechanism that is mutually exclusive for either H3K4me3 or H3K27me3. Furthermore, we show a genome-wide co-localization of SHL with H3K27me3 and H3K4me3, and that BAH-H3K27me3 and PHD-H3K4me3 interactions are important for SHL-mediated floral repression. Together, our study establishes BAH-PHD cassette as a dual histone methyl-lysine binding module that is distinct from others in recognizing both active and repressive histone marks. 1 Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA. 2 Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53706, USA. 3 National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Center for Plant Stress Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201602, China. -
The Arabidopsis LHP1 Protein Is a Component of Euchromatin
Planta (2005) 222: 910–925 DOI 10.1007/s00425-005-0129-4 ORIGINAL ARTICLE Marc Libault Æ Federico Tessadori Æ Sophie Germann Berend Snijder Æ Paul Fransz Æ Vale´rie Gaudin The Arabidopsis LHP1 protein is a component of euchromatin Received: 11 June 2005 / Accepted: 29 August 2005 / Published online: 22 October 2005 Ó Springer-Verlag 2005 Abstract The HP1 family proteins are involved in several A. thaliana HP1 homolog with the mammal HP1c iso- aspects of chromatin function and regulation in Dro- form, besides specific plant properties. sophila, mammals and the fission yeast. Here we inves- tigate the localization of LHP1, the unique Arabidopsis Keywords Arabidopsis Æ Chromatin Æ Heterochromatin thaliana HP1 homolog known at present time, to ap- protein 1 Æ Mitosis Æ Nucleolus proach its function. A functional LHP1–GFP fusion protein, able to restore the wild-type phenotype in the Abbreviations PI: Propidium iodide Æ DAPI: lhp1 mutant, was used to analyze the subnuclear distri- 4¢,6-diamidino-2-phenylindole Æ HP1: Heterochromatin bution of LHP1 in both A. thaliana and Nicotiana protein 1 Æ CD: Chromo domain Æ CSD: Chromo tabacum.InA. thaliana interphase nuclei, LHP1 was shadow domain Æ HR: Hinge region Æ RHF: Relative predominantly located outside the heterochromatic heterochromatin fraction Æ FISH: Fluorescent in-situ chromocenters. No major aberrations were observed in hybridization Æ NLS: Nuclear localization heterochromatin content or chromocenter organization signal Æ NoLS: Nucleolar localization signal in lhp1 plants. These data indicate that LHP1 is mainly involved in euchromatin organization in A. thaliana.In tobacco BY-2 cells, the LHP1 distribution, although in foci, slightly differed suggesting that LHP1 localization Introduction is determined by the underlying genome organization of plant species. -
Chromatin Condensation and Recruitment of PHD Finger Proteins
6102–6112 Nucleic Acids Research, 2016, Vol. 44, No. 13 Published online 25 March 2016 doi: 10.1093/nar/gkw193 Chromatin condensation and recruitment of PHD finger proteins to histone H3K4me3 are mutually exclusive Jovylyn Gatchalian1,†, Carmen Mora Gallardo2,†, Stephen A. Shinsky3, Ruben Rosas Ospina1, Andrea Mansilla Liendo2, Krzysztof Krajewski3, Brianna J. Klein1, Forest H. Andrews1, Brian D. Strahl3, Karel H. M. van Wely2,* and Tatiana G. Kutateladze1,* 1Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA, 2Department of Immunology and Oncology, Centro Nacional de Biotecnolog´ıa/CSIC, 28049 Madrid, Spain and 3Department of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA Received January 06, 2016; Revised March 12, 2016; Accepted March 15, 2016 ABSTRACT modifications (PTMs), including acetylation and methyla- tion of lysine, methylation of arginine, and phosphorylation Histone post-translational modifications, and spe- of serine and threonine. Over 500 histone PTMs have been cific combinations they create, mediate a wide range identified by mass spectrometry analysis, and a number of of nuclear events. However, the mechanistic bases these modifications, or epigenetic marks, have been shown for recognition of these combinations have not been to modulate chromatin structure and cell cycle specific pro- elucidated. Here, we characterize crosstalk between cesses (1). H3T3 and H3T6 phosphorylation, occurring in mito- Methylation of histone H3 at lysine 4 is one of the canon- sis, and H3K4me3, a mark associated with active ical PTMs (2–4). The trimethylated species (H3K4me3), transcription. We detail the molecular mechanisms which is found primarily in active promoters, is impli- by which H3T3ph/K4me3/T6ph switches mediate ac- cated in transcriptional regulation (5). -
CHEMICAL GENETIC and EPIGENETICS: Chemical Probes for Methyl Lysine Reader Domains
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Curr Opin Manuscript Author Chem Biol. Author Manuscript Author manuscript; available in PMC 2017 August 01. Published in final edited form as: Curr Opin Chem Biol. 2016 August ; 33: 135–141. doi:10.1016/j.cbpa.2016.06.004. CHEMICAL GENETIC AND EPIGENETICS: Chemical probes for methyl lysine reader domains Lindsey I. James and Stephen V. Frye Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 125 Mason Farm Road, Marsico Hall, UNC-Chapel Hill, NC 27599-7363 Abstract The primary intent of a chemical probe is to establish the relationship between a molecular target, usually a protein whose function is modulated by the probe, and the biological consequences of that modulation. In order to fulfill this purpose, a chemical probe must be profiled for selectivity, mechanism of action, and cellular activity, as the cell is the minimal system in which ‘biology’ can be explored. This review provides a brief overview of progress toward chemical probes for methyl lysine reader domains with a focus on recent progress targeting chromodomains. Introduction Advances in understanding the regulation of chromatin accessibility via post-translational modifications (PTMs) of histones have rejuvenated drug discovery directed toward modulation of transcription as the opportunities for pharmacological intervention are significantly better than direct perturbation of transcription factors [1–3]. Chemical biology is poised to play a central role in advancing scientific knowledge and assessing therapeutic opportunities in chromatin regulation. Specifically, cell penetrant, high-quality chemical probes that influence chromatin state are of great significance [4,5]. -
Structural Basis for Specific Binding of Polycomb Chromodomain to Histone H3 Methylated at Lys 27
Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION Reinberg 2001; Lachner and Jenuwein 2002): They meth- Structural basis for specific ylate various lysine residues located at the flexible N binding of Polycomb termini of histones H3 and H4. Methylation of different lysine residues has differential biological effects. To de- chromodomain to histone H3 cipher the histone code generated by lysine methylation, methylated at Lys 27 it is important to understand the mechanism by which the various methyl-lysine signals are differentially rec- Jinrong Min,1 Yi Zhang,2 and Rui-Ming Xu1,3 ognized by the cellular machinery. Two well-studied chromatin-regulated biological pro- 1W.M. Keck Structural Biology Laboratory, Cold Spring cesses are position effect variegation (PEV) and homeotic Harbor Laboratory, Cold Spring Harbor, New York 11724, gene silencing in Drosophila. Heterochromatin forma- USA; 2Department of Biochemistry and Biophysics, tion in PEV is associated with methylation of Lys 9 of Lineberger Comprehensive Cancer Center, University of histone H3 by SU(VAR)3-9 and its homologs (Rea et al. North Carolina at Chapel Hill, North Carolina 27599, USA 2000). Methylation of Lys 27 of histone H3 by a multi- protein complex containing Enhancer of Zeste, E(z), and The chromodomain of Drosophila Polycomb protein is Extra Sex Combs (ESC), or their human counterparts essential for maintaining the silencing state of homeotic EZH2and EED, are associated with the repression of genes during development. Recent studies suggest that homeotic genes (Cao et al. 2002; Czermin et al. 2002; Polycomb mediates the assembly of repressive higher- Kuzmichev et al. -
Methylation of Histone H3 at Lysine 4 Is Highly Conserved and Correlates with Transcriptionally Active Nuclei in Tetrahymena
Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena Brian D. Strahl*, Reiko Ohba*, Richard G. Cook†, and C. David Allis*‡ *Department of Biochemistry and Molecular Genetics, University of Virginia Health Science Center, Charlottesville, VA 22908; and †Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX 77030 Communicated by Joseph G. Gall, Carnegie Institution of Washington, Baltimore, MD, October 15, 1999 (received for review May 18, 1999) Studies into posttranslational modifications of histones, notably acet- ences appear to exist (1, 10). Interestingly, each modified lysine ylation, have yielded important insights into the dynamic nature of has the capacity to be mono-, di-, or trimethylated, adding yet chromatin structure and its fundamental role in gene expression. The another level of variation to this posttranslational ‘‘mark’’ (1, 11). roles of other covalent histone modifications remain poorly under- The role(s) of histone methylation have remained elusive al- stood. To gain further insight into histone methylation, we investi- though several reports suggest that this modification may play a gated its occurrence and pattern of site utilization in Tetrahymena, functional role, albeit undefined, in gene transcription (11–14). yeast, and human HeLa cells. In Tetrahymena, transcriptionally active To date, little information exists on the major enzyme systems macronuclei, but not transcriptionally inert micronuclei, contain a responsible -
University of California
UNIVERSITY OF CALIFORNIA Los Angeles H3K36 methylation and the chromodomain protein Eaf3 are required for proper cotranscriptional spliceosome assembly A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Molecular Biology by Calvin Siu Leung 2019 © Copyright by Calvin Siu Leung 2019 ABSTRACT OF THE DISSERTATION H3K36 methylation and the chromodomain protein Eaf3 are required for proper cotranscriptional spliceosome assembly by Calvin Siu Leung Doctor of Philosophy in Molecular Biology University of California, Los Angeles, 2019 Professor Tracy L. Johnson, Chair In the nucleus of the eukaryotic cell, spliceosome assembly and the subsequent catalytic steps of precursor RNA (pre-mRNA) splicing occur cotranscriptionally in the context of a dynamic chromatin environment. A key challenge in the field has been to understand the role that chromatin and, more specifically, histone modification plays in coordinating transcription and splicing. Despite previous work to decipher the coordination between these processes, a mechanistic understanding of the role that chromatin modification plays in spliceosome assembly has remained elusive. Histone H3K36 trimethylation (H3K36me3) is a highly conserved histone mark found in the body of actively transcribed genes, making it a particularly attractive candidate for having a role in the regulation of pre-mRNA splicing. Although there have been reports that H3K36me3 influences alternative splicing, the underlying mechanisms have remained elusive. Moreover, ii despite the prevalence of this mark on actively transcribed genes across eukaryotes, there has not been a mechanistic dissection of its potential role in constitutive splicing. Here we describe how we have addressed these questions and uncovered a core role for H3K36 methylation (H3K36me) in splicing in Saccharomyces cerevisiae (S. -
The Role of Bromodomain Proteins in Regulating Gene Expression
Genes 2012, 3, 320-343; doi:10.3390/genes3020320 OPEN ACCESS genes ISSN 2073-4425 www.mdpi.com/journal/genes Review The Role of Bromodomain Proteins in Regulating Gene Expression Gabrielle A. Josling, Shamista A. Selvarajah, Michaela Petter and Michael F. Duffy * Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Australia; E-Mails: [email protected] (G.A.J.); [email protected] (S.A.S.); [email protected] (M.P.) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +61-38344-3262; Fax: +61-39347-1863. Received: 30 April 2012; in revised form: 11 May 2012 / Accepted: 17 May 2012 / Published: 29 May 2012 Abstract: Histone modifications are important in regulating gene expression in eukaryotes. Of the numerous histone modifications which have been identified, acetylation is one of the best characterised and is generally associated with active genes. Histone acetylation can directly affect chromatin structure by neutralising charges on the histone tail, and can also function as a binding site for proteins which can directly or indirectly regulate transcription. Bromodomains specifically bind to acetylated lysine residues on histone tails, and bromodomain proteins play an important role in anchoring the complexes of which they are a part to acetylated chromatin. Bromodomain proteins are involved in a diverse range of functions, such as acetylating histones, remodeling chromatin, and recruiting other factors necessary for transcription. These proteins thus play a critical role in the regulation of transcription. Keywords: bromodomain; histone acetylation; histone modifications; histone code; epigenetics 1. Introduction The post-translational modification of histones plays an important role in regulating gene expression in eukaryotes. -
Deregulation of Histone H3 Lysine 27 Methylation in Cancer—Different Paths, Same Destination
Published OnlineFirst July 1, 2014; DOI: 10.1158/1078-0432.CCR-13-2499 Clinical Cancer Molecular Pathways Research Molecular Pathways: Deregulation of Histone H3 Lysine 27 Methylation in Cancer—Different Paths, Same Destination Teresa Ezponda and Jonathan D. Licht Abstract Methylation of lysine 27 on histone H3 (H3K27me), a modification associated with gene repression, plays a critical role in regulating the expression of genes that determine the balance between cell differentiation and proliferation. Alteration of the level of this histone modification has emerged as a recurrent theme in many types of cancer, demonstrating that either excess or lack of H3K27 methylation can have oncogenic effects. Cancer genome sequencing has revealed the genetic basis of H3K27me deregulation, including mutations of the components of the H3K27 methyltransferase complex PRC2 and accessory proteins, and deletions and inactivating mutations of the H3K27 demethylase UTX in a wide variety of neoplasms. More recently, mutations of lysine 27 on histone H3 itself were shown to prevent H3K27me in pediatric glioblastomas. Aberrant expression or mutations in proteins that recognize H3K27me3 also occur in cancer and may result in misinterpretation of this mark. In addition, due to the cross-talk between different epigenetic modifications, alterations of chromatin modifiers controlling H3K36me, or even mutations of this residue, can ultimately regulate H3K27me levels and distribution across the genome. The significance of mutations altering H3K27me is underscored by the fact that many tumors harboring such lesions often have a poor clinical outcome. New therapeutic approaches targeting aberrant H3K27 methylation include small molecules that block the action of mutant EZH2 in germinal center-derived lymphoma. -
Basis of Specificity for a Conserved and Promiscuous Chromatin
RESEARCH ARTICLE Basis of specificity for a conserved and promiscuous chromatin remodeling protein Drake A Donovan1, Johnathan G Crandall1, Vi N Truong1, Abigail L Vaaler1, Thomas B Bailey1, Devin Dinwiddie1, Orion GB Banks1, Laura E McKnight1*, Jeffrey N McKnight1,2 1Institute of Molecular Biology, University of Oregon, Eugene, United States; 2Phil and Penny Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, United States Abstract Eukaryotic genomes are organized dynamically through the repositioning of nucleosomes. Isw2 is an enzyme that has been previously defined as a genome-wide, nonspecific nucleosome spacing factor. Here, we show that Isw2 instead acts as an obligately targeted nucleosome remodeler in vivo through physical interactions with sequence-specific factors. We demonstrate that Isw2-recruiting factors use small and previously uncharacterized epitopes, which direct Isw2 activity through highly conserved acidic residues in the Isw2 accessory protein Itc1. This interaction orients Isw2 on target nucleosomes, allowing for precise nucleosome positioning at targeted loci. Finally, we show that these critical acidic residues have been lost in the Drosophila lineage, potentially explaining the inconsistently characterized function of Isw2-like proteins. Altogether, these data suggest an ‘interacting barrier model,’ where Isw2 interacts with a sequence-specific factor to accurately and reproducibly position a single, targeted nucleosome to define the precise border of phased chromatin arrays. *For correspondence: [email protected] Introduction Chromatin consists of the nucleic acids and proteins that make up the functional genome of all Competing interests: The eukaryotic organisms. The most basic regulatory and structural unit of chromatin is the nucleosome. authors declare that no Each nucleosome is defined as an octamer of histone proteins, which is wrapped by approximately competing interests exist.