Epigenetic Modifications Precede Molecular Alterations and Drive Human Hepatocarcinogenesis
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
The MAP4K4-STRIPAK Complex Promotes Growth and Tissue Invasion In
bioRxiv preprint doi: https://doi.org/10.1101/2021.05.07.442906; this version posted May 8, 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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder.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. 1 The MAP4K4-STRIPAK complex promotes growth and tissue invasion in 2 medulloblastoma 3 Jessica Migliavacca1, Buket Züllig1, Charles Capdeville1, Michael Grotzer2 and Martin Baumgartner1,* 4 1 Division of Oncology, Children’s Research Center, University Children’s Hospital Zürich, Zürich, 5 Switzerland 6 2 Division of Oncology, University Children’s Hospital Zürich, Zürich, Switzerland 7 8 *e-mail: [email protected] 9 10 Abstract 11 Proliferation and motility are mutually exclusive biological processes associated with cancer that depend 12 on precise control of upstream signaling pathways with overlapping functionalities. We find that STRN3 13 and STRN4 scaffold subunits of the STRIPAK complex interact with MAP4K4 for pathway regulation in 14 medulloblastoma. Disruption of the MAP4K4-STRIPAK complex impairs growth factor-induced 15 migration and tissue invasion and stalls YAP/TAZ target gene expression and oncogenic growth. The 16 migration promoting functions of the MAP4K4-STRIPAK complex involve the activation of novel PKCs 17 and the phosphorylation of the membrane targeting S157 residue of VASP through MAP4K4. The anti- 18 proliferative effect of complex disruption is associated with reduced YAP/TAZ target gene expression 19 and results in repressed tumor growth in the brain tissue. This dichotomous functionality of the STRIPAK 20 complex in migration and proliferation control acts through MAP4K4 regulation in tumor cells and 21 provides relevant mechanistic insights into novel tumorigenic functions of the STRIPAK complex in 22 medulloblastoma. -
Molecular Effects of Isoflavone Supplementation Human Intervention Studies and Quantitative Models for Risk Assessment
Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis committee Promotors Prof. Dr Pieter van ‘t Veer Professor of Nutritional Epidemiology Wageningen University Prof. Dr Evert G. Schouten Emeritus Professor of Epidemiology and Prevention Wageningen University Co-promotors Dr Anouk Geelen Assistant professor, Division of Human Nutrition Wageningen University Dr Lydia A. Afman Assistant professor, Division of Human Nutrition Wageningen University Other members Prof. Dr Jaap Keijer, Wageningen University Dr Hubert P.J.M. Noteborn, Netherlands Food en Consumer Product Safety Authority Prof. Dr Yvonne T. van der Schouw, UMC Utrecht Dr Wendy L. Hall, King’s College London This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). Molecular effects of isoflavone supplementation Human intervention studies and quantitative models for risk assessment Vera van der Velpen Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 20 June 2014 at 13.30 p.m. in the Aula. Vera van der Velpen Molecular effects of isoflavone supplementation: Human intervention studies and quantitative models for risk assessment 154 pages PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN: 978-94-6173-952-0 ABSTRact Background: Risk assessment can potentially be improved by closely linked experiments in the disciplines of epidemiology and toxicology. -
Associated 16P11.2 Deletion in Drosophila Melanogaster
ARTICLE DOI: 10.1038/s41467-018-04882-6 OPEN Pervasive genetic interactions modulate neurodevelopmental defects of the autism- associated 16p11.2 deletion in Drosophila melanogaster Janani Iyer1, Mayanglambam Dhruba Singh1, Matthew Jensen1,2, Payal Patel 1, Lucilla Pizzo1, Emily Huber1, Haley Koerselman3, Alexis T. Weiner 1, Paola Lepanto4, Komal Vadodaria1, Alexis Kubina1, Qingyu Wang 1,2, Abigail Talbert1, Sneha Yennawar1, Jose Badano 4, J. Robert Manak3,5, Melissa M. Rolls1, Arjun Krishnan6,7 & 1234567890():,; Santhosh Girirajan 1,2,8 As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of indi- vidual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interac- tions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes. 1 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. 2 Bioinformatics and Genomics Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. -
Downloaded the “Top Edge” Version
bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 2019. 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 4.0 International license. 1 Drosophila models of pathogenic copy-number variant genes show global and 2 non-neuronal defects during development 3 Short title: Non-neuronal defects of fly homologs of CNV genes 4 Tanzeen Yusuff1,4, Matthew Jensen1,4, Sneha Yennawar1,4, Lucilla Pizzo1, Siddharth 5 Karthikeyan1, Dagny J. Gould1, Avik Sarker1, Yurika Matsui1,2, Janani Iyer1, Zhi-Chun Lai1,2, 6 and Santhosh Girirajan1,3* 7 8 1. Department of Biochemistry and Molecular Biology, Pennsylvania State University, 9 University Park, PA 16802 10 2. Department of Biology, Pennsylvania State University, University Park, PA 16802 11 3. Department of Anthropology, Pennsylvania State University, University Park, PA 16802 12 4 contributed equally to work 13 14 *Correspondence: 15 Santhosh Girirajan, MBBS, PhD 16 205A Life Sciences Building 17 Pennsylvania State University 18 University Park, PA 16802 19 E-mail: [email protected] 20 Phone: 814-865-0674 21 1 bioRxiv preprint doi: https://doi.org/10.1101/855338; this version posted December 6, 2019. 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 4.0 International license. 22 ABSTRACT 23 While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non- 24 neuronal phenotypes, functional studies evaluating these regions have focused on the molecular 25 basis of neuronal defects. -
Novel Pharmacological Maps of Protein Lysine Methyltransferases: Key for Target Deorphanization Obdulia Rabal* , Andrea Castellar and Julen Oyarzabal*
Rabal et al. J Cheminform (2018) 10:32 https://doi.org/10.1186/s13321-018-0288-5 RESEARCH ARTICLE Open Access Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization Obdulia Rabal* , Andrea Castellar and Julen Oyarzabal* Abstract Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and autoinmune diseases. Among the diferent epigenetic target families, protein lysine methyltransferases (PKMTs), are especially interesting because it is believed that their inhibition may be highly specifc at the functional level. Despite its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of the PKMT family. Accordingly, the identifcation of chemical probes for the validation of the therapeutic impact of epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specifc- ity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacologi- cal similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the prediction of ligand of-target efects caused by lack of ligand selectivity and the repurposing of known compounds against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here, we frst perform a systematic study of binding modes of cofactor and substrate bound ligands with all available SET domain-containing PKMTs. Protein ligand interaction fngerprints were applied to identify conserved hot spots and contact-specifc residues across subfamilies at each binding site; a relevant analysis for guiding the design of novel, selective compounds. Then, a recently described methodology (GPCR-CoINPocket) that incorporates ligand contact information into classical alignment-based comparisons was applied to the entire family of 50 SET-containing proteins to devise pharmacological similarities between them. -
WO 2012/174282 A2 20 December 2012 (20.12.2012) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/174282 A2 20 December 2012 (20.12.2012) P O P C T (51) International Patent Classification: David [US/US]; 13539 N . 95th Way, Scottsdale, AZ C12Q 1/68 (2006.01) 85260 (US). (21) International Application Number: (74) Agent: AKHAVAN, Ramin; Caris Science, Inc., 6655 N . PCT/US20 12/0425 19 Macarthur Blvd., Irving, TX 75039 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 14 June 2012 (14.06.2012) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, English (25) Filing Language: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, Publication Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (30) Priority Data: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 61/497,895 16 June 201 1 (16.06.201 1) US MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 61/499,138 20 June 201 1 (20.06.201 1) US OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 61/501,680 27 June 201 1 (27.06.201 1) u s SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/506,019 8 July 201 1(08.07.201 1) u s TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. -
Treatments for Ankyloglossia and Ankyloglossia with Concomitant Lip-Tie Comparative Effectiveness Review Number 149
Comparative Effectiveness Review Number 149 Treatments for Ankyloglossia and Ankyloglossia With Concomitant Lip-Tie Comparative Effectiveness Review Number 149 Treatments for Ankyloglossia and Ankyloglossia With Concomitant Lip-Tie Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-2012-00009-I Prepared by: Vanderbilt Evidence-based Practice Center Nashville, TN Investigators: David O. Francis, M.D., M.S. Sivakumar Chinnadurai, M.D., M.P.H. Anna Morad, M.D. Richard A. Epstein, Ph.D., M.P.H. Sahar Kohanim, M.D. Shanthi Krishnaswami, M.B.B.S., M.P.H. Nila A. Sathe, M.A., M.L.I.S. Melissa L. McPheeters, Ph.D., M.P.H. AHRQ Publication No. 15-EHC011-EF May 2015 This report is based on research conducted by the Vanderbilt Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2012-00009-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. -
Sequence Specificity Analysis of the SETD2 Protein Lysine Methyltransferase and Discovery of a SETD2 Super-Substrate
ARTICLE https://doi.org/10.1038/s42003-020-01223-6 OPEN Sequence specificity analysis of the SETD2 protein lysine methyltransferase and discovery of a SETD2 super-substrate Maren Kirstin Schuhmacher1,4, Serap Beldar2,4, Mina S. Khella1,3,4, Alexander Bröhm1, Jan Ludwig1, ✉ ✉ 1234567890():,; Wolfram Tempel2, Sara Weirich1, Jinrong Min2 & Albert Jeltsch 1 SETD2 catalyzes methylation at lysine 36 of histone H3 and it has many disease connections. We investigated the substrate sequence specificity of SETD2 and identified nine additional peptide and one protein (FBN1) substrates. Our data showed that SETD2 strongly prefers amino acids different from those in the H3K36 sequence at several positions of its specificity profile. Based on this, we designed an optimized super-substrate containing four amino acid exchanges and show by quantitative methylation assays with SETD2 that the super-substrate peptide is methylated about 290-fold more efficiently than the H3K36 peptide. Protein methylation studies confirmed very strong SETD2 methylation of the super-substrate in vitro and in cells. We solved the structure of SETD2 with bound super-substrate peptide con- taining a target lysine to methionine mutation, which revealed better interactions involving three of the substituted residues. Our data illustrate that substrate sequence design can strongly increase the activity of protein lysine methyltransferases. 1 Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany. 2 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada. 3 Biochemistry Department, Faculty of Pharmacy, Ain Shams University, African Union Organization Street, Abbassia, Cairo 11566, Egypt. 4These authors contributed equally: Maren Kirstin Schuhmacher, Serap Beldar, Mina S. -
STRIPAK Directs PP2A Activity Toward MAP4K4 to Promote Oncogenic Transformation of Human Cells
RESEARCH ARTICLE STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation of human cells Jong Wook Kim1,2,3,4†, Christian Berrios2,5†, Miju Kim1,2†, Amy E Schade2,5†, Guillaume Adelmant6,7,8, Huwate Yeerna3, Emily Damato1, Amanda Balboni Iniguez1,9, Laurence Florens10, Michael P Washburn10,11, Kim Stegmaier1,9, Nathanael S Gray6, Pablo Tamayo3,4, Ole Gjoerup2, Jarrod A Marto6,7,8, James DeCaprio2,5,12*, William C Hahn1,2,12* 1Broad Institute of Harvard and MIT, Cambridge, United States; 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States; 3Division of Medical Genetics, School of Medicine, University of California, San Diego, San Diego, United States; 4Moores Cancer Center, University of California, San Diego, San Diego, United States; 5Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, United States; 6Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States; 7Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States; 8Department of Oncologic Pathology, Dana- Farber Cancer Institute, Boston, United States; 9Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, United States; 10Stowers Institute for Medical Research, Kansas City, United States; 11Department of Pathology and Laboratory *For correspondence: Medicine, University of Kansas Medical Center, Kansas City, United States; 12 [email protected] Department of Medicine, Brigham and Women’s Hospital and Harvard Medical (JDC); School, Boston, United States [email protected] (WCH) †These authors contributed equally to this work Abstract Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers, and partial loss of PP2A function contributes to cell transformation. -
NSD1) Methyltransferase in Coordinating Lysine 36 Methylation at Histone 3 with RNA Polymerase II Function
Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function Agda Karina Lucio-Eterovica, Melissa M. Singha,1, Jeffrey E. Gardnera, Chendhore S. Veerappanb, Judd C. Riceb, and Phillip B. Carpentera,2 aDepartment of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX 77030; and bDepartment of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033 Edited* by George R. Stark, Lerner Research Institute NE2, Cleveland, OH, and approved August 19, 2010 (received for review March 2, 2010) The NSD (nuclear receptor-binding SET domain protein) family proteins behave as oncogenes in AML, but inactivation of NSD1 in encodes methyltransferases that are important in multiple aspects neuroblastomas behaves as a tumor suppressor (3). In addition to of development and disease. Perturbations in NSD family mem- its role in development and cancer, NSD1 is haploinsufficient in bers can lead to Sotos syndrome and Wolf–Hirschhorn syndrome Sotos syndrome (11), a childhood overgrowth disease character- as well as cancers such as acute myeloid leukemia. Previous studies ized by a broad set of phenotypes, including macrocephaly, ad- have implicated NSD1 (KMT3B) in transcription and methylation of vanced bone age, facial dymorphism, learning disabilities, and histone H3 at lysine 36 (H3-K36), but its molecular mechanism in seizures (12). these processes remains largely unknown. Here we describe an Histone side chains undergo a plethora of posttranslational modifications (PTMs) that formulate a “histone code” (13–15). NSD1 regulatory network in human cells. -
STRIPAK Directs PP2A Activity Toward MAP4K4 to Promote Oncogenic Transformation
bioRxiv preprint doi: https://doi.org/10.1101/823096; this version posted October 29, 2019. 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 4.0 International license. STRIPAK directs PP2A activity toward MAP4K4 to promote oncogenic transformation Jong Wook Kim1,2,7,8*, Christian Berrios2,4*, Miju Kim1,2*, Amy E. Schade2,4*, Guillaume Adelmant5, Huwate Yeerna7, Emily Damato1, Amanda Balboni Iniguez1,6, Selene K. Swanson9, Laurence Florens9, Michael P. Washburn9.10, Kim Stegmaier1,6, Nathaniel S. Gray5, Pablo Tamayo7,8, Ole Gjoerup2, Jarrod A. Marto5, James A. DeCaprio2,3,4,†, William C. Hahn1, 2, 3,† 1Broad Institute of Harvard and MIT, Cambridge MA. 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA. 3Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA. 4Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA. 5Department of Cancer Biology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston MA. 6Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston MA. 7Division of Medical Genetics, School of Medicine, UC San Diego, CA. 8Moores Cancer Center, University of California, San Diego, CA. 9Stowers Institute for Medical Research, Kansas City, MO 64110 10Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160 * These authors contributed equally to the work. †Co-senior authors 1 bioRxiv preprint doi: https://doi.org/10.1101/823096; this version posted October 29, 2019. -
Genetics of Lipedema: New Perspectives on Genetic Research and Molecular Diagnoses S
European Review for Medical and Pharmacological Sciences 2019; 23: 5581-5594 Genetics of lipedema: new perspectives on genetic research and molecular diagnoses S. PAOLACCI1, V. PRECONE2, F. ACQUAVIVA3, P. CHIURAZZI4,5, E. FULCHERI6,7, M. PINELLI3,8, F. BUFFELLI9,10, S. MICHELINI11, K.L. HERBST12, V. UNFER13, M. BERTELLI2; GENEOB PROJECT 1MAGI’S LAB, Rovereto (TN), Italy 2MAGI EUREGIO, Bolzano, Italy 3Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, Italy 4Istituto di Medicina Genomica, Fondazione A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy 5UOC Genetica Medica, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy 6Fetal and Perinatal Pathology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy 7Department of Integrated Surgical and Diagnostic Sciences, University of Genoa, Genoa, Italy 8Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy 9Fetal and Perinatal Pathology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy 10Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences, University of Genoa, Genoa, Italy 11Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Rome, Italy 12Department of Medicine, University of Arizona, Tucson, AZ, USA 13Department of Developmental and Social Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy Abstract. – OBJECTIVE: The aim of this quali- Introduction tative review is to provide an update on the cur- rent understanding of the genetic determinants of lipedema and to develop a genetic test to dif- Lipedema is an underdiagnosed chronic debil- ferentiate lipedema from other diagnoses. itating disease characterized by bruising and pain MATERIALS AND METHODS: An electronic and excess of subcutaneous adipose tissue of the search was conducted in MEDLINE, PubMed, and legs and/or arms in women during or after times Scopus for articles published in English up to of hormone change, especially in puberty1.