DOCSLIB.ORG

Regulating Methylation at H3K27: a Trick Or Treat for Cancer Cell Plasticity

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulating Methylation at H3K27: a Trick Or Treat for Cancer Cell Plasticity cancers Review Regulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity Provas Das and Joseph H. Taube * Department of Biology, Baylor University, Waco, TX 76706, USA; [email protected] * Correspondence: [email protected] Received: 29 August 2020; Accepted: 23 September 2020; Published: 29 September 2020 Simple Summary: Regulation of gene expression is important for appropriate cell development but can also lead to inappropriate cell transformation resulting in cancer. Modification to the proteins that wrap DNA is essential for regulating gene expression. Mutations in the enzymes that modify such proteins are being discovered in many cancers. This review will cover present knowledge of these enzymes as they relate to cancer initiation and progression. Abstract: Properly timed addition and removal of histone 3 lysine 27 tri-methylation (H3K27me3) is critical for enabling proper differentiation throughout all stages of development and, likewise, can guide carcinoma cells into altered differentiation states which correspond to poor prognoses and treatment evasion. In early embryonic stages, H3K27me3 is invoked to silence genes and restrict cell fate. Not surprisingly, mutation or altered functionality in the enzymes that regulate this pathway results in aberrant methylation or demethylation that can lead to malignancy. Likewise, changes in expression or activity of these enzymes impact cellular plasticity, metastasis, and treatment evasion. This review focuses on current knowledge regarding methylation and de-methylation of H3K27 in cancer initiation and cancer cell plasticity. Keywords: H3K27me3; EZH2; KDM6A; KDM6B; cancer cell plasticity 1. Introduction Regulation of gene expression depends on access to the genome and recruitment of trans-acting factors, both of which are processes that are impacted by the histone modification state. Modification of specific histones can be pathologically altered by aberrant “writers” that add modifications, “erasers” that remove modifications, or by the mutation of the histone structure which can prevent the residues from being modified [1,2]. Along with these modifications, alteration in the “readers” can alter the functional outcome of the modification. Tri-methylation of the 27th lysine residue on histone H3 (H3K27me3), while just one of many such modifications, plays an important role in developmentally driven gene silencing and in cancer initiation and progression. This review will cover present knowledge on the role of H3K27me3 and the enzymes which modify this residue in cancer, with a particular focus on cellular plasticity. 2. Histone Methylation and Demethylation: An Historical Perspective Although largely thought of as a genetic disease, current evidence establishes that epigenetic aberrations can play profound and ubiquitous roles in cancer origin and progression [3–5]. Results from large-scale cancer genome sequencing projects describe that an unanticipated 50% of human cancers harbor mutations in chromatin-related proteins [6,7]. Overwhelming evidence supports the notion that specific genetic, environmental, and metabolic stimuli can disrupt the homeostatic balance in chromatin machinery, which can cause either aberrantly restrictive or permissive responses. Such stimuli can Cancers 2020, 12, 2792; doi:10.3390/cancers12102792 www.mdpi.com/journal/cancers CancersCancers2020 2020, 12, ,12 2792 2 of2 of 33 32 responses. Such stimuli can act on quiescent or premalignant cells to promote malignancy and/or acttumor on quiescent cells to hasten or premalignant their progression cells to and promote adaptation. malignancy The ubiquity and/or tumor of such cells stimuli to hasten means their that progressionepigenetic anddefects adaptation. are involved The ubiquity in various of suchaspects stimuli of cancer means [8–10]. that epigenetic defects are involved in variousHistone aspects modifications, of cancer [8–10 DNA]. methylation, chromatin architecture, and the expression of non- codingHistone transcripts modifications, drive the DNAepigenetic methylation, state of a ce chromatinll. The N-terminal architecture, tails of and histones the expression can undergo of a non-codingvariety of transcriptspost-translati driveonal the covalent epigenetic modifications state of a cell. which The can N-terminal then impact tails ofcritical histones DNA-dependent can undergo a varietyprocesses of post-translationallike replication, transcription, covalent modifications and repair which [11,12]. can thenHistone impact methylation critical DNA-dependent is mediated by processesmethyltransferases like replication, that catalyze transcription, the mono-, and di-, repair or tri- [11 methylation,12]. Histone of specific methylation residues. is mediated Dynamic byand methyltransferasesreversible methylation that catalyzeof histones the plays mono-, an important di-, or tri- role methylation in the regulation of specific of gene residues. expression. Dynamic Two andmajor reversible families methylation of histone of methyltransferases histones plays an importantare lysine role methyltransferases in the regulation (KMTs) of gene expression.and protein Twoarginine major methyltransferases families of histone methyltransferases(PRMTs). Whereas aremeth lysineylation methyltransferases of some lysine residues (KMTs) andis associated protein argininewith activation methyltransferases of gene transcription (PRMTs). Whereas (e.g., H3K4 methylation, H3K36, and of some H3K79), lysine methylation residues is associatedof other residues with activationis associated of gene with transcription repression of (e.g., gene H3K4, transcript H3K36,ion (e.g., and H3K79),H3K9, H3K20, methylation and H3K27) of other [13–15]. residues Some is associatedhistone modifications with repression are of enriched gene transcription at distinct (e.g.,regions H3K9, (i.e., H3K20, enhancer and, promoter, H3K27) [13 or–15 coding]. Some sequences) histone modificationsof the gene, though are enriched H3K27me3 at distinct is distributed regions (i.e.,wide enhancer,ly across enhancers promoter, and orcoding promoters sequences) [16]. Moreover, of the gene,mono-, though di-, H3K27me3or tri-methylation is distributed of a single widely residue across enhancerscan alter the and affinity promoters of “reader” [16]. Moreover, proteins mono-, to the di-,methylated or tri-methylation histones ofand a singlemay have residue distinct can alterfunctional the affi consequencesnity of “reader” [17]. proteins to the methylated histonesIn andparticular, may have tri-methylation distinct functional of the consequenceslysine at the 27th [17]. amino acid on histone H3 (H3K27me3) is a criticalIn particular, determinant tri-methylation of chroma oftin the accessibility lysine at the and 27th gene amino expression. acid on histoneThe “writer” H3 (H3K27me3) of H3K27me3, is aenhancer critical determinant of zeste 2 (EZH2) of chromatin (Figure accessibility 1), has been and known gene to expression. be involved The in “writer”tumor progression of H3K27me3, in an enhanceroncogenic of zestecapacity 2 (EZH2) for over (Figure twenty1), hasyears been [18–20] known. Detailed to be involved reviews in concerning tumor progression the activity in anand oncogenichistory of capacity the H3K27me3 for over methyltransferases, twenty years [18– 20EZH1]. Detailed and EZH2, reviews are available concerning [21,22]. the activityNevertheless, and historythe more of the recent H3K27me3 uncovering methyltransferases, of Jumonji-domain-containing EZH1 and EZH2, proteins, are available which are [21 capable,22]. Nevertheless, of catalyzing thethe more demethylation recent uncovering of H3K27me3, of Jumonji-domain-containing has revealed additional proteins, complexity which are capablesurrounding of catalyzing H3K27me3 the demethylation(Figure 1). of H3K27me3, has revealed additional complexity surrounding H3K27me3 (Figure1). FigureFigure 1. Regulated1. Regulated addition addition and removaland removal of H3K27me3 of H3K27me3 is critical foris maintainingcritical for cellularmaintaining homeostasis. cellular Functioninghomeostasis. as membersFunctioning of protein as members complexes, of protein the indicated complexes, enzymes the possessindicated the enzymes biochemical possess activity the tobiochemical alter the methylation activity to state alter at the H3K27 methylation while chromodomain-containing state at H3K27 while chromodomain-containing proteins, among others, haveproteins, the capacity among toothers, interpret have the the methylation capacity to state. interpret Disruption the methylation in this balance, state. whetherDisruption through in this mutationsbalance, (indicatedwhether through by strikethroughs), mutations (indicated altered recruitment by striketh (indicatedroughs), altered by change recruitment in nucleosome (indicated color), by over-expressionchange in nucleosome (indicated color), by additional over-expression boxes) or under-expression(indicated by additional (indicated boxes) by fewer or under-expression boxes), has the potential(indicated to driveby fewer and/ orboxes), support has tumorigenesis the potential through to drive the and/or expansion support of cell tumorigenesis fate identity. through the expansion of cell fate identity. Cancers 2020, 12, 2792 3 of 33 2.1. Molecular Mechanisms The primary H3K27me3 “writer” protein, EZH2, is the enzymatic component of the polycomb repressor complex 2 (PRC2) and is capable of catalyzing methylation of non-methylated H3K27 to either a di- or tri-methylated state. The C-terminal SET domain
Load more

Recommended publications
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • O-Glcnacylation Regulates the Stability and Enzymatic Activity of the Histone Methyltransferase EZH2
    O-GlcNAcylation regulates the stability and enzymatic activity of the histone methyltransferase EZH2 Pei-Wen Loa, Jiun-Jie Shieb, Chein-Hung Chena, Chung-Yi Wua, Tsui-Ling Hsua, and Chi-Huey Wonga,1 aGenomics Research Center, Academia Sinica, Taipei 115, Taiwan; and bInstitute of Chemistry, Academia Sinica, Taipei 115, Taiwan Contributed by Chi-Huey Wong, May 16, 2018 (sent for review February 1, 2018; reviewed by Michael D. Burkart, Benjamin G. Davis, and Gerald W. Hart) Protein O-glycosylation by attachment of β-N-acetylglucosamine maintenance and differentiation in embryonic stem cells (14, 15). (GlcNAc) to the Ser or Thr residue is a major posttranslational It was suggested that O-GlcNAcylation might play an important glycosylation event and is often associated with protein folding, role in the regulation of PRC1-mediated gene expression, and stability, and activity. The methylation of histone H3 at Lys-27 along this line the O-GlcNAcylation of EZH2 at S76 in the PRC2 catalyzed by the methyltransferase EZH2 was known to suppress complex was reported to stablize EZH2 in our previous study (16). gene expression and cancer development, and we previously The PRC2 complex is composed of Enhancer of zeste 2 (EZH2), reported that the O-GlcNAcylation of EZH2 at S76 stabilized Suppressor of Zeste 12 (Suz12), Extraembryonic endoderm (EED), EZH2 and facilitated the formation of H3K27me3 to inhibit tumor AE binding protein 2 (AEBP2), and retinoblastoma binding protein suppression. In this study, we employed a fluorescence-based method 4/7 (RBBP4/7) (17, 18). Within the PRC2 complex, EZH2 catalyzes the di- and trimethylation of histone H3 at lysine 27 (K27) to form of sugar labeling combined with mass spectrometry to investigate H3K27me2/3 to regulate embryonic and cancer development EZH2 glycosylation and identified five O-GlcNAcylation sites.
    [Show full text]
  • Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
    cells Review Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin Agnieszka Bochy ´nska,Juliane Lüscher-Firzlaff and Bernhard Lüscher * ID Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany; [email protected] (A.B.); jluescher-fi[email protected] (J.L.-F.) * Correspondence: [email protected]; Tel.: +49-241-8088850; Fax: +49-241-8082427 Received: 18 January 2018; Accepted: 27 February 2018; Published: 2 March 2018 Abstract: Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex.
    [Show full text]
  • The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
    cancers Review The Mutational Landscape of Myeloid Leukaemia in Down Syndrome Carini Picardi Morais de Castro 1, Maria Cadefau 1,2 and Sergi Cuartero 1,2,* 1 Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; [email protected] (C.P.M.d.C); [email protected] (M.C.) 2 Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain * Correspondence: [email protected] Simple Summary: Leukaemia occurs when specific mutations promote aberrant transcriptional and proliferation programs, which drive uncontrolled cell division and inhibit the cell’s capacity to differentiate. In this review, we summarize the most frequent genetic lesions found in myeloid leukaemia of Down syndrome, a rare paediatric leukaemia specific to individuals with trisomy 21. The evolution of this disease follows a well-defined sequence of events and represents a unique model to understand how the ordered acquisition of mutations drives malignancy. Abstract: Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and Citation: de Castro, C.P.M.; Cadefau, in signalling mediators of the JAK/STAT and RAS pathways.
    [Show full text]
  • Modeling of Histone Modifications Reveals Formation Mechanism and Function of Bivalent Chromatin
    bioRxiv preprint doi: https://doi.org/10.1101/2021.02.03.429504; this version posted February 3, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Modeling of histone modifications reveals formation mechanism and function of bivalent chromatin Wei Zhao1,2, Lingxia Qiao1, Shiyu Yan2, Qing Nie3,*, Lei Zhang1,2,* 1 Beijing International Center for Mathematical Research, Peking University, Beijing 100871, China 2 Center for Quantitative Biology, Peking University, Beijing 100871, China 3 Department of Mathematics and Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA. *Corresponding authors: Qing Nie, email: [email protected]; Lei Zhang, email: [email protected] Abstract Bivalent chromatin is characterized by occupation of both activating histone modifications and repressive histone modifications. While bivalent chromatin is known to link with many biological processes, the mechanisms responsible for its multiple functions remain unclear. Here, we develop a mathematical model that involves antagonistic histone modifications H3K4me3 and H3K27me3 to capture the key features of bivalent chromatin. Three necessary conditions for the emergence of bivalent chromatin are identified, including advantageous methylating activity over demethylating activity, frequent noise conversions of modifications, and sufficient nonlinearity. The first condition is further confirmed by analyzing the
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Epigenetic Regulation of Promiscuous Gene Expression in Thymic Medullary Epithelial Cells
    Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells Lars-Oliver Tykocinskia,1,2, Anna Sinemusa,1, Esmail Rezavandya, Yanina Weilandb, David Baddeleyb, Christoph Cremerb, Stephan Sonntagc, Klaus Willeckec, Jens Derbinskia, and Bruno Kyewskia,3 aDivision of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center, D-69120 Heidelberg, Germany; bKirchhoff Institute for Physics, University of Heidelberg, D-69120 Heidelberg, Germany; and cInstitute for Genetics, University of Bonn, D-53117 Bonn, Germany Edited* by Philippa Marrack, National Jewish Health, Denver, CO, and approved September 28, 2010 (received for review July 2, 2010) Thymic central tolerance comprehensively imprints the T-cell re- ing of delimited regions allowing access of general and specific ceptor repertoire before T cells seed the periphery. Medullary transcriptional factors to act on gene-specific control elements thymic epithelial cells (mTECs) play a pivotal role in this process by (8). This scenario is clearly different from the intricate regulation virtue of promiscuous expression of tissue-restricted autoantigens. of functionally related gene families like the Hox gene locus or β The molecular regulation of this unusual gene expression, in the -globin gene locus (9). A similar phenomenon as observed in Drosophila particular the involvement of epigenetic mechanisms is only poorly has been reported for housekeeping genes but not for understood. By studying promiscuous expression of the mouse TRAs in vertebrates (10). casein locus, we report that transcription of this locus proceeds Here we analyzed the interrelationship between emerging gene expression patterns at the single cell level, promoter-associated from a delimited region (“entry site”) to increasingly complex pat- epigenetic marks, and the differentiation of mTECs in the murine terns along with mTEC maturation.
    [Show full text]
  • Clinical Utility of Recently Identified Diagnostic, Prognostic, And
    Modern Pathology (2017) 30, 1338–1366 1338 © 2017 USCAP, Inc All rights reserved 0893-3952/17 $32.00 Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms Arantza Onaindia1, L Jeffrey Medeiros2 and Keyur P Patel2 1Instituto de Investigacion Marques de Valdecilla (IDIVAL)/Hospital Universitario Marques de Valdecilla, Santander, Spain and 2Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA Genomic profiling studies have provided new insights into the pathogenesis of mature B-cell neoplasms and have identified markers with prognostic impact. Recurrent mutations in tumor-suppressor genes (TP53, BIRC3, ATM), and common signaling pathways, such as the B-cell receptor (CD79A, CD79B, CARD11, TCF3, ID3), Toll- like receptor (MYD88), NOTCH (NOTCH1/2), nuclear factor-κB, and mitogen activated kinase signaling, have been identified in B-cell neoplasms. Chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and marginal zone lymphomas of splenic, nodal, and extranodal types represent examples of B-cell neoplasms in which novel molecular biomarkers have been discovered in recent years. In addition, ongoing retrospective correlative and prospective outcome studies have resulted in an enhanced understanding of the clinical utility of novel biomarkers. This progress is reflected in the 2016 update of the World Health Organization classification of lymphoid neoplasms, which lists as many as 41 mature B-cell neoplasms (including provisional categories). Consequently, molecular genetic studies are increasingly being applied for the clinical workup of many of these neoplasms. In this review, we focus on the diagnostic, prognostic, and/or therapeutic utility of molecular biomarkers in mature B-cell neoplasms.
    [Show full text]
  • Recognition of Cancer Mutations in Histone H3K36 by Epigenetic Writers and Readers Brianna J
    EPIGENETICS https://doi.org/10.1080/15592294.2018.1503491 REVIEW Recognition of cancer mutations in histone H3K36 by epigenetic writers and readers Brianna J. Kleina, Krzysztof Krajewski b, Susana Restrepoa, Peter W. Lewis c, Brian D. Strahlb, and Tatiana G. Kutateladzea aDepartment of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA; bDepartment of Biochemistry & Biophysics, The University of North Carolina School of Medicine, Chapel Hill, NC, USA; cWisconsin Institute for Discovery, University of Wisconsin, Madison, WI, USA ABSTRACT ARTICLE HISTORY Histone posttranslational modifications control the organization and function of chromatin. In Received 30 May 2018 particular, methylation of lysine 36 in histone H3 (H3K36me) has been shown to mediate gene Revised 1 July 2018 transcription, DNA repair, cell cycle regulation, and pre-mRNA splicing. Notably, mutations at or Accepted 12 July 2018 near this residue have been causally linked to the development of several human cancers. These KEYWORDS observations have helped to illuminate the role of histones themselves in disease and to clarify Histone; H3K36M; cancer; the mechanisms by which they acquire oncogenic properties. This perspective focuses on recent PTM; methylation advances in discovery and characterization of histone H3 mutations that impact H3K36 methyla- tion. We also highlight findings that the common cancer-related substitution of H3K36 to methionine (H3K36M) disturbs functions of not only H3K36me-writing enzymes but also H3K36me-specific readers. The latter case suggests that the oncogenic effects could also be linked to the inability of readers to engage H3K36M. Introduction from yeast to humans and has been shown to have a variety of functions that range from the control Histone proteins are main components of the of gene transcription and DNA repair, to cell cycle nucleosome, the fundamental building block of regulation and nutrient stress response [8].
    [Show full text]
  • Automethylation of PRC2 Promotes H3K27 Methylation and Is Impaired in H3K27M Pediatric Glioma
    Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma Chul-Hwan Lee,1,2,7 Jia-Ray Yu,1,2,7 Jeffrey Granat,1,2,7 Ricardo Saldaña-Meyer,1,2 Joshua Andrade,3 Gary LeRoy,1,2 Ying Jin,4 Peder Lund,5 James M. Stafford,1,2,6 Benjamin A. Garcia,5 Beatrix Ueberheide,3 and Danny Reinberg1,2 1Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA; 2Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA; 3Proteomics Laboratory, New York University School of Medicine, New York, New York 10016, USA; 4Shared Bioinformatics Core, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; 5Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/ EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring inde- pendently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2.
    [Show full text]
  • A Flexible Microfluidic System for Single-Cell Transcriptome Profiling
    www.nature.com/scientificreports OPEN A fexible microfuidic system for single‑cell transcriptome profling elucidates phased transcriptional regulators of cell cycle Karen Davey1,7, Daniel Wong2,7, Filip Konopacki2, Eugene Kwa1, Tony Ly3, Heike Fiegler2 & Christopher R. Sibley 1,4,5,6* Single cell transcriptome profling has emerged as a breakthrough technology for the high‑resolution understanding of complex cellular systems. Here we report a fexible, cost‑efective and user‑ friendly droplet‑based microfuidics system, called the Nadia Instrument, that can allow 3′ mRNA capture of ~ 50,000 single cells or individual nuclei in a single run. The precise pressure‑based system demonstrates highly reproducible droplet size, low doublet rates and high mRNA capture efciencies that compare favorably in the feld. Moreover, when combined with the Nadia Innovate, the system can be transformed into an adaptable setup that enables use of diferent bufers and barcoded bead confgurations to facilitate diverse applications. Finally, by 3′ mRNA profling asynchronous human and mouse cells at diferent phases of the cell cycle, we demonstrate the system’s ability to readily distinguish distinct cell populations and infer underlying transcriptional regulatory networks. Notably this provided supportive evidence for multiple transcription factors that had little or no known link to the cell cycle (e.g. DRAP1, ZKSCAN1 and CEBPZ). In summary, the Nadia platform represents a promising and fexible technology for future transcriptomic studies, and other related applications, at cell resolution. Single cell transcriptome profling has recently emerged as a breakthrough technology for understanding how cellular heterogeneity contributes to complex biological systems. Indeed, cultured cells, microorganisms, biopsies, blood and other tissues can be rapidly profled for quantifcation of gene expression at cell resolution.
    [Show full text]
  • Polycomb Repressor Complex 2 Function in Breast Cancer (Review)
    INTERNATIONAL JOURNAL OF ONCOLOGY 57: 1085-1094, 2020 Polycomb repressor complex 2 function in breast cancer (Review) COURTNEY J. MARTIN and ROGER A. MOOREHEAD Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada Received July 10, 2020; Accepted September 7, 2020 DOI: 10.3892/ijo.2020.5122 Abstract. Epigenetic modifications are important contributors 1. Introduction to the regulation of genes within the chromatin. The poly- comb repressive complex 2 (PRC2) is a multi‑subunit protein Epigenetic modifications, including DNA methylation complex that is involved in silencing gene expression through and histone modifications, play an important role in gene the trimethylation of lysine 27 at histone 3 (H3K27me3). The regulation. The dysregulation of these modifications can dysregulation of this modification has been associated with result in pathogenicity, including tumorigenicity. Research tumorigenicity through the increased repression of tumour has indicated an important influence of the trimethylation suppressor genes via condensing DNA to reduce access to the modification at lysine 27 on histone H3 (H3K27me3) within transcription start site (TSS) within tumor suppressor gene chromatin. This methylation is involved in the repression promoters. In the present review, the core proteins of PRC2, as of multiple genes within the genome by condensing DNA well as key accessory proteins, will be described. In addition, to reduce access to the transcription start site (TSS) within mechanisms controlling the recruitment of the PRC2 complex gene promoter sequences (1). The recruitment of H1.2, an H1 to H3K27 will be outlined. Finally, literature identifying the histone subtype, by the H3K27me3 modification has been a role of PRC2 in breast cancer proliferation, apoptosis and suggested as a mechanism for mediating this compaction (1).
    [Show full text]