H3.3K27M Mutant Proteins Reprogram Epigenome by Sequestering The
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Dedifferentiation by Adenovirus E1A Due to Inactivation of Hippo Pathway Effectors YAP and TAZ
Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Dedifferentiation by adenovirus E1A due to inactivation of Hippo pathway effectors YAP and TAZ Nathan R. Zemke, Dawei Gou, and Arnold J. Berk Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA Adenovirus transformed cells have a dedifferentiated phenotype. Eliminating E1A in transformed human embryonic kidney cells derepressed ∼2600 genes, generating a gene expression profile closely resembling mesenchymal stem cells (MSCs). This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers, and actomyosin-dependent flat- tening against the substratum. E1A-induced hypoacetylation at histone H3 Lys27 and Lys18 (H3K27/18) was reversed. Most of the increase in H3K27/18ac was in enhancers near TEAD transcription factors bound by Hippo signaling-regulated coactivators YAP and TAZ. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei, where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required RHO family GTPase signaling and caused histone acetylation by p300/CBP, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then superenhancers. Consistent results were also observed in primary rat embryo kidney cells, human fibroblasts, and human respiratory tract epithelial cells. These results together with earlier studies suggest that YAP/TAZ function in a developmental checkpoint controlled by signaling from the actin cytoskeleton that prevents differ- entiation of a progenitor cell until it is in the correct cellular and tissue environment. -
DNA Methylation Regulates Discrimination of Enhancers From
Sharifi-Zarchi et al. BMC Genomics (2017) 18:964 DOI 10.1186/s12864-017-4353-7 RESEARCHARTICLE Open Access DNA methylation regulates discrimination of enhancers from promoters through a H3K4me1-H3K4me3 seesaw mechanism Ali Sharifi-Zarchi1,2,3,4†, Daniela Gerovska5†, Kenjiro Adachi6, Mehdi Totonchi3, Hamid Pezeshk7,8, Ryan J. Taft9, Hans R. Schöler6,10, Hamidreza Chitsaz2, Mehdi Sadeghi8,11, Hossein Baharvand3,12* and Marcos J. Araúzo-Bravo5,13,14* Abstract Background: DNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers. Results: We investigated the relationship between DNA methylation and active chromatin marks through genome- wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci. We hypothesized “seesaw” dynamics between H3K4me1 and H3K4me3 in the low and intermediate DNA methylation range, in which DNA methylation discriminates between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively. Low methylated regions are H3K4me3 enriched, while those with intermediate DNA methylation levels are progressively H3K4me1 enriched. Additionally, the enrichment of H3K27ac, distinguishing active from primed enhancers, follows a plateau in the lower range of the intermediate DNA methylation level, corresponding to active enhancers, and decreases linearly in the higher range of the intermediate DNA methylation. Thus, the decrease of the DNA methylation switches smoothly the state of the enhancers from a primed to an active state. -
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. -
The Landscape of Somatic Mutations in Epigenetic Regulators Across 1,000 Paediatric Cancer Genomes
ARTICLE Received 24 Sep 2013 | Accepted 12 Mar 2014 | Published 8 Apr 2014 DOI: 10.1038/ncomms4630 The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes Robert Huether1,*, Li Dong2,*, Xiang Chen1, Gang Wu1, Matthew Parker1, Lei Wei1, Jing Ma2, Michael N. Edmonson1, Erin K. Hedlund1, Michael C. Rusch1, Sheila A. Shurtleff2, Heather L. Mulder3, Kristy Boggs3, Bhavin Vadordaria3, Jinjun Cheng2, Donald Yergeau3, Guangchun Song2, Jared Becksfort1, Gordon Lemmon1, Catherine Weber2, Zhongling Cai2, Jinjun Dang2, Michael Walsh4, Amanda L. Gedman2, Zachary Faber2, John Easton3, Tanja Gruber2,4, Richard W. Kriwacki5, Janet F. Partridge6, Li Ding7,8,9, Richard K. Wilson7,8,9, Elaine R. Mardis7,8,9, Charles G. Mullighan2, Richard J. Gilbertson10, Suzanne J. Baker10, Gerard Zambetti6, David W. Ellison2, Jinghui Zhang1 & James R. Downing2 Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. -
Tsrna Signatures in Cancer
tsRNA signatures in cancer Veronica Balattia, Giovanni Nigitaa,1, Dario Venezianoa,1, Alessandra Druscoa, Gary S. Steinb,c, Terri L. Messierb,c, Nicholas H. Farinab,c, Jane B. Lianb,c, Luisa Tomaselloa, Chang-gong Liud, Alexey Palamarchuka, Jonathan R. Harte, Catherine Belle, Mariantonia Carosif, Edoardo Pescarmonaf, Letizia Perracchiof, Maria Diodorof, Andrea Russof, Anna Antenuccif, Paolo Viscaf, Antonio Ciardig, Curtis C. Harrish, Peter K. Vogte, Yuri Pekarskya,2, and Carlo M. Crocea,2 aDepartment of Cancer Biology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; bDepartment of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405; cUniversity of Vermont Cancer Center, College of Medicine, Burlington, VT 05405; dMD Anderson Cancer Center, Houston, TX 77030; eDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; fIstituto di Ricovero e Cura a Carattere Scientifico, Regina Elena National Cancer Institute, 00144 Rome, Italy; gUniversita’ Di Roma La Sapienza, 00185 Rome, Italy; and hLaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Contributed by Carlo M. Croce, June 13, 2017 (sent for review April 26, 2017; reviewed by Riccardo Dalla-Favera and Philip N. Tsichlis) Small, noncoding RNAs are short untranslated RNA molecules, some these molecules, which we defined as single-stranded small of which have been associated with cancer development. Recently RNAs, 16–48 nt long, ending with a stretch of four Ts (4). When we showed that a class of small RNAs generated during the matu- tsRNAs accumulate in the nucleus, they can be exported, sug- ration process of tRNAs (tRNA-derived small RNAs, hereafter gesting that tsRNAs could regulate gene expression at different “tsRNAs”) is dysregulated in cancer. -
M2139: Molecular Analysis for Gliomas
Molecular Analysis for Gliomas Policy Number: AHS – M2139 – Molecular Analysis Prior Policy Name and Number, as applicable: for Gliomas • AHS – M2139 – Analysis of MGMT Promoter Methylation for Malignant Gliomas Initial Presentation Date: 06/16/2021 Revision Date: N/A I. Policy Description Glioma refers to tumors resulting from metaplastic transformation of glial tissue of the nervous system. Tumors have historically been classified by the retained histologic features of the three types of glial cells: astrocytes, oligodendrocytes, and ependymal cells. Tumors of each type can vary widely in aggressiveness, response to treatment, and prognosis (Louis, Schiff, & Batchelor, 2020). Molecular genetic features were added to histopathologic appearance in the current WHO classification to yield more biologically homogeneous and narrowly defined diagnostic entities for greater diagnostic accuracy, improved patient management, more accurate determinations of prognosis, and better treatment response (Louis et al., 2016). II. Related Policies Policy Number Policy Title AHS-M2109 Molecular Panel Testing of Cancers for Diagnosis, Prognosis, and Identification of Targeted Therapy III. Indications and/or Limitations of Coverage Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request 1. MGMT promoter methylation testing IS MEDICALLY NECESSARY for prognosis of malignant gliomas. 2. IDH1 and IDH2 testing IS MEDICALLY NECESSARY for prognosis of malignant gliomas. M2139 Molecular Analysis for Gliomas Page 1 of 15 3. Testing for the co-deletion of 1p and 19q by either fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) for the characterization of gliomas and/or to guide treatment decisions IS MEDICALLY NECESSARY. 4. ATRX mutation testing via EITHER immunohistochemistry OR gene sequencing IS MEDICALLY NECESSARY for the prognosis of malignant gliomas. -
Snf2h-Mediated Chromatin Organization and Histone H1 Dynamics Govern Cerebellar Morphogenesis and Neural Maturation
ARTICLE Received 12 Feb 2014 | Accepted 15 May 2014 | Published 20 Jun 2014 DOI: 10.1038/ncomms5181 OPEN Snf2h-mediated chromatin organization and histone H1 dynamics govern cerebellar morphogenesis and neural maturation Matı´as Alvarez-Saavedra1,2, Yves De Repentigny1, Pamela S. Lagali1, Edupuganti V.S. Raghu Ram3, Keqin Yan1, Emile Hashem1,2, Danton Ivanochko1,4, Michael S. Huh1, Doo Yang4,5, Alan J. Mears6, Matthew A.M. Todd1,4, Chelsea P. Corcoran1, Erin A. Bassett4, Nicholas J.A. Tokarew4, Juraj Kokavec7, Romit Majumder8, Ilya Ioshikhes4,5, Valerie A. Wallace4,6, Rashmi Kothary1,2, Eran Meshorer3, Tomas Stopka7, Arthur I. Skoultchi8 & David J. Picketts1,2,4 Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation. -
Genome-Wide Screen of Cell-Cycle Regulators in Normal and Tumor Cells
bioRxiv preprint doi: https://doi.org/10.1101/060350; this version posted June 23, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Genome-wide screen of cell-cycle regulators in normal and tumor cells identifies a differential response to nucleosome depletion Maria Sokolova1, Mikko Turunen1, Oliver Mortusewicz3, Teemu Kivioja1, Patrick Herr3, Anna Vähärautio1, Mikael Björklund1, Minna Taipale2, Thomas Helleday3 and Jussi Taipale1,2,* 1Genome-Scale Biology Program, P.O. Box 63, FI-00014 University of Helsinki, Finland. 2Science for Life laboratory, Department of Biosciences and Nutrition, Karolinska Institutet, SE- 141 83 Stockholm, Sweden. 3Science for Life laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden To identify cell cycle regulators that enable cancer cells to replicate DNA and divide in an unrestricted manner, we performed a parallel genome-wide RNAi screen in normal and cancer cell lines. In addition to many shared regulators, we found that tumor and normal cells are differentially sensitive to loss of the histone genes transcriptional regulator CASP8AP2. In cancer cells, loss of CASP8AP2 leads to a failure to synthesize sufficient amount of histones in the S-phase of the cell cycle, resulting in slowing of individual replication forks. Despite this, DNA replication fails to arrest, and tumor cells progress in an elongated S-phase that lasts several days, finally resulting in death of most of the affected cells. -
The Genetic Landscape of Ganglioglioma Melike Pekmezci1, Javier E
Pekmezci et al. Acta Neuropathologica Communications (2018) 6:47 https://doi.org/10.1186/s40478-018-0551-z RESEARCH Open Access The genetic landscape of ganglioglioma Melike Pekmezci1, Javier E. Villanueva-Meyer2, Benjamin Goode1, Jessica Van Ziffle1,3, Courtney Onodera1,3, James P. Grenert1,3, Boris C. Bastian1,3, Gabriel Chamyan4, Ossama M. Maher5, Ziad Khatib5, Bette K. Kleinschmidt-DeMasters6, David Samuel7, Sabine Mueller8,9,10, Anuradha Banerjee8,9, Jennifer L. Clarke10,11, Tabitha Cooney12, Joseph Torkildson12, Nalin Gupta8,9, Philip Theodosopoulos9, Edward F. Chang9, Mitchel Berger9, Andrew W. Bollen1, Arie Perry1,9, Tarik Tihan1 and David A. Solomon1,3* Abstract Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. -
Somatic Histone H3 Alterations in Pediatric Diffuse Intrinsic Pontine
BRIEF COMMUNICATIONS (c.83A>T) in H3F3A resulting in a substitution to methionine at lysine 27 Somatic histone H3 alterations in (p.Lys27Met) in the histone H3.3 protein (Supplementary Fig. 1). In the tumor from a fifth affected individual, an analogous adenine-to- pediatric diffuse intrinsic pontine thymine transversion (c.83A>T) encoding a p.Lys27Met alteration was gliomas and non-brainstem identified in the closely related HIST1H3B gene, which codes for the histone H3.1 isoform. glioblastomas To determine the frequency of mutations in the histone H3 gene family, we performed targeted sequencing of the exons encoding Lys27 in all 16 1,8 2,8 3,8 Gang Wu , Alberto Broniscer , Troy A McEachron , genes that code for histone H3 isoforms in a validation cohort comprising 4 3 5 5 Charles Lu , Barbara S Paugh , Jared Becksfort , Chunxu Qu , 43 DIPGs as well as 36 non-BS-PGs (see Supplementary Methods and 4 1 1 3 Li Ding , Robert Huether , Matthew Parker , Junyuan Zhang , Supplementary Tables 1 and 2). Including the original seven individuals 2 3 6 Amar Gajjar , Michael A Dyer , Charles G Mullighan , with DIPG analyzed by WGS, we found recurrent adenine-to-thymine 3 4 4 Richard J Gilbertson , Elaine R Mardis , Richard K Wilson , transversions encoding p.Lys27Met alterations in H3F3A or HIST1H3B in 6 6 1 James R Downing , David W Ellison , Jinghui Zhang & 78% of DIPGs and 22% of non-BS-PGs (Fig. 1 and Table 1). In addition, 3 Suzanne J Baker for the St. Jude Children’s Research Hospital– a new guanine-to-adenine transition resulting in a p.Gly34Arg alteration 7 Washington University Pediatric Cancer Genome Project in H3F3A was identified in 5 of 36 (14%) non-BS-PGs but not in any of the 50 DIPGs analyzed. -
Enhancer Priming by H3K4 Methylation Safeguards Germline Competence
bioRxiv preprint doi: https://doi.org/10.1101/2020.07.07.192427; this version posted July 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Title: Enhancer priming by H3K4 methylation safeguards germline competence 1* 1 1,2 Authors: Tore Bleckwehl , Kaitlin Schaaf , Giuliano Crispatzu , Patricia 1,3 1,4 5 5 Respuela , Michaela Bartusel , Laura Benson , Stephen J. Clark , Kristel M. 6 7 1,8 7,9 Dorighi , Antonio Barral , Magdalena Laugsch , Miguel Manzanares , Joanna 6,10,11 5,12,13 1,3,14* Wysocka , Wolf Reik , Álvaro Rada-Iglesias Affiliations: 1 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany. 2 Department of Internal Medicine 2, University Hospital Cologne. 3 Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/University of Cantabria, Spain. 4 Department of Biology, Massachusetts Institute of Technology, USA. 5 Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK. 6 Department of Chemical and Systems Biology, Stanford University School of Medicine, USA. 7 Centro Nacional de Investigaciones Cardiovasculares (CNIC), Spain. 8 Institute of Human Genetics, Heidelberg University Hospital, Germany. 9 Centro de Biología Molecular Severo Ochoa (CBMSO), CSIC-UAM, Spain. 10 Department of Developmental Biology, Stanford University School of Medicine, USA. 11 Howard Hughes Medical Institute, Stanford University School of Medicine, USA. 12 Centre for Trophoblast Research, University of Cambridge, CB2 3EG, UK 13 Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK. -
Detection of H3K27M Mutation in Cases of Brain Stem Subependymoma
Human Pathology (2019) 84,262–269 www.elsevier.com/locate/humpath Original contribution Detection of H3K27M mutation in cases of brain stem subependymoma☆ Kun Yao MD a,1, Zejun Duan MS a,1, Yin Wang MD b, Mingshan Zhang MD c, Tao Fan MD c, Bin Wu BS c, Xueling Qi BS a,⁎ aDepartment of Pathology, San Bo Brain Hospital, Capital Medical University, Haidian District, Beijing, China bDepartment of Pathology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China cDepartment of Neurosurgery, San Bo Brain Hospital, Capital Medical University, Haidian District, Beijing, China Received 5 August 2018; revised 2 October 2018; accepted 11 October 2018 Keywords: Summary Subependymomas are rare, slow-growing, grade I glial tumors of the central nervous system. Re- H3K27M mutation; cently, diffuse midline gliomas with mutations in the H3.1 or H3.3 genes at the position of amino acid 27, Subependymoma; resulting in the replacement of lysine by methionine (K27M), were defined as the new grade IV entity. As Brain stem neoplasm; H3K27M mutations have been reported in midline gliomas, gangliogliomas, and pilocytic astrocytomas, Sanger sequencing whether they occur in midline subependymomas has been unclear. We determined whether any such muta- tions can be found in them and analyzed the prognostic relevance of any such mutations in subependymo- mas. Four subependymomas, all in the brain stem, harbored H3K27M mutations. No such mutation was found in any of the subependymomas from other locations. The mutations were identified by immunohisto- chemical stains and confirmed with Sanger sequencing. The median follow-up of the patients with the mutations in their tumors was 3.2 years, and 3 are still alive, having received no adjuvant therapy.