DOCSLIB.ORG

Prodromal Variability in Huntington's Disease Progression and Resistance

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Prodromal Variability in Huntington's Disease Progression and Resistance Georgia State University ScholarWorks @ Georgia State University Neuroscience Institute Dissertations Neuroscience Institute 8-7-2018 Prodromal Variability in Huntington's Disease Progression and Resistance Jennifer Ciarochi Follow this and additional works at: https://scholarworks.gsu.edu/neurosci_diss Recommended Citation Ciarochi, Jennifer, "Prodromal Variability in Huntington's Disease Progression and Resistance." Dissertation, Georgia State University, 2018. https://scholarworks.gsu.edu/neurosci_diss/39 This Dissertation is brought to you for free and open access by the Neuroscience Institute at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Neuroscience Institute Dissertations by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. PRODROMAL VARIABILITY IN HUNTINGTON’S DISEASE PROGRESSION AND RESISTANCE by JENNIFER CIAROCHI Under the Direction of Jessica Turner, Ph.D. ABSTRACT Huntington’s disease (HD) is a neurodegenerative movement disorder caused by abnormal cytosine-adenine-guanine (CAG) expansion on the HTT gene. As both a proteinopathy and the most common PolyQ disease, HD shares key features with several disorders that disproportionately affect the growing elderly population in the United States, including delayed- onset, selective neuronal death, and protein misfolding. Across these conditions, there are few treatments and no known cures; however, their shared features suggest common underlying mechanisms, and delayed-onset hints at possible prevention or reversal. CAG-expansion-number and age are related to diagnosis and can be used to estimate age-of-onset for prodromal (pre- diagnosis) individuals, who possess the causal mutation but have not manifested diagnosis- associated motor symptoms. Over a decade before diagnosis, prodromal individuals differ from controls in brain structure and connectivity, cognition, and motor functioning. Although age and CAG-number account for most observed variability in HD-onset, persons with identical CAG- numbers often develop symptoms at different ages, indicating that additional genetic and environmental factors also mediate decline. Little is known about detrimental and protective genetic factors in HD. Studying prodromal progression can inform interventions by highlighting early prevention targets. This research leverages advanced multivariate techniques applied to legacy PREDICT- HD data to characterize brain structure, cognition, and motor functioning across prodromal HD and investigate genetic factors accounting for variability in these domains. Regarding brain structure, these experiments provide evidence for: regional co-occurrence in prodromal decline, early fronto-striatal degradation, dorso-ventral reduction gradients, and delayed atrophy in certain movement-related and subcortical regions. The genetic findings suggest a protective role of NTRK2 and identify NCOR1 and ADORA2B variants with early, CAG-independent detrimental effects on gray matter. Previously identified onset-delaying variants are also confirmed as CAG-independent modulators of brain structure and clinical functioning. Clinical findings highlight motor functioning as the best indicator of brain-structural integrity until the late prodrome and demonstrate that distinct regions coincide with cognitive compared to motor functioning; furthermore, regions that most align with clinical functioning vary at different prodromal stages. INDEX WORDS: Huntington’s disease, Genetic modifiers, Multivariate methods, Prodromal symptoms, Disease progression, Brain-derived neurotrophic factor, Tropomyosin receptor kinase B, Supplementary motor, Independent component analysis PRODROMAL VARIABILITY IN HUNTINGTON’S DISEASE PROGRESSION AND RESISTANCE by JENNIFER CIAROCHI A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the College of Arts and Sciences Georgia State University 2018 Copyright by Jennifer Ashley Ciarochi 2018 PRODROMAL VARIABILITY IN HUNTINGTON’S DISEASE PROGRESSION AND RESISTANCE by JENNIFER CIAROCHI Committee Chair: Jessica Turner Committee: Jingyu Liu Daniel Cox Mukesh Dhamala Electronic Version Approved: Office of Graduate Studies College of Arts and Sciences Georgia State University August 2018 iv DEDICATION To the 1,449 people who generously participated in the PREDICT-HD study, in many cases over several years and with no obvious direct benefit to themselves. Their committed involvement has and will continue to enable great advancements in our understanding of Huntington’s Disease, providing hope for a cure for future generations. v ACKNOWLEDGEMENTS Several entities contributed to the success of this project; notably, my committee members (Drs. Jessica Turner, Jingyu Liu, Daniel Cox, and Mukesh Dhamala) have been exceedingly patient with my procrastination, spotty scheduling capabilities, and verbose writing style (as evidenced by this absurdly long dissertation), and I am grateful for their guidance over the years. Dr. Turner has been a wonderful advisor, donating her time whenever it is needed (despite her obscenely busy schedule) and readily demonstrating patience and level-headedness in a field that is often anything but. She is more organized than I could ever hope to be, and none of this would have been possible without her. Dr. Liu has patiently worked with me over the years, on a weekly basis, to nurture my understanding of imaging, genetics, and ICA-based techniques and has several times greatly assisted in interpreting the results of these experiments. Dr. Cox has been steadfastly supportive of my often overly-ambitious research agenda, and has enabled me to take this research a step further by addressing my questions in the context of a wet-lab environment; despite my inexperience, I have learned so much from him about studying disease in Drosophila. Dr. Dhamala has supported my professional development in the classroom, on my qualifying exam committee, and again during my dissertation proposal and defense, and has never once complained. Again, I cannot thank my committee enough for their time and support. This work would also not be possible without my co-authors and the PREDICT-HD researchers and contributors from across the globe who diligently worked to amass such a comprehensive dataset from a rare clinical population. Of particular note are Jane S. Paulsen, the PREDICT-HD principal investigator who generously shared her expertise and data at all levels of this project; Hans Johnson, who provided guidance and R code that I would not have had a vi snowball’s chance in hell of generating myself on this timeline; and Vince Calhoun, who first made ICA approachable and may respond to e-mails faster than any other human on the planet. I would also like to thank my parents (both biological and otherwise), not only for my literal existence but for nurturing my interests, never saying no when I asked for a book, and always encouraging me to be my best rather than the best, even when that meant I never did my homework. My brother Nick also deserves mentioning; he has always been there to remind me that I am, indeed, not the best. Aside from those who encouraged me to succeed, I owe my gratitude to those who helped me relax; these include the writers of several trashy Netflix shows that will not be named here (and the people who dubbed them in Spanish), NPR’s written news for providing a slightly less depressing alternative to their radio news (and for overusing the word “imbroglio” when discussing Russia), the man who must have donated hours of his time pronouncing words for Dictionary.com (I’m looking at you, “imbroglio”), that one old man who seems to narrate every free audio book (from Aesop’s Fables to Plato’s Republic), GrubHub delivery drivers, Beyoncé (obviously), pizza (obviously), and the White House (for providing a steady stream of drama during lulls in available Netflix material). Last, but certainly not least, I would like to thank my significant other (Aaron) for his unwavering support and at least six months of groceries, as well as his geriatric dog (Dakota), who is smacking me as I write this. vii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................ V LIST OF TABLES ....................................................................................................... XVI LIST OF FIGURES .................................................................................................. XVIII LIST OF ABBREVIATIONS ....................................................................................... XX 1 INTRODUCTION ...................................................................................................... 1 1.1 Background .......................................................................................................... 1 1.2 Prodromal Brain Structure and Clinical Functioning..................................... 3 1.3 Genetic Modifiers of Prodromal Symptoms ..................................................... 5 1.4 Purpose of the Study ........................................................................................... 7 1.4.1 Experiment 1 ................................................................................................... 7 1.4.2 Experiment 2 ................................................................................................... 8 1.4.3 Experiment 3 ..................................................................................................
Load more

Recommended publications
  • 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]
  • Genome-Wide Profiling of Active Enhancers in Colorectal Cancer
    Genome-wide proling of active enhancers in colorectal cancer Min Wu ( [email protected] ) Wuhan University https://orcid.org/0000-0003-1372-4764 Qinglan Li Wuhan University Xiang Lin Wuhan University Ya-Li Yu Zhongnan Hospital, Wuhan University Lin Chen Wuhan University Qi-Xin Hu Wuhan University Meng Chen Zhongnan Hospital, Wuhan University Nan Cao Zhongnan Hospital, Wuhan University Chen Zhao Wuhan University Chen-Yu Wang Wuhan University Cheng-Wei Huang Wuhan University Lian-Yun Li Wuhan University Mei Ye Zhongnan Hospital, Wuhan University https://orcid.org/0000-0002-9393-3680 Article Keywords: Colorectal cancer, H3K27ac, Epigenetics, Enhancer, Transcription factors Posted Date: December 10th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-119156/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Genome-wide profiling of active enhancers in colorectal cancer Qing-Lan Li1, #, Xiang Lin1, #, Ya-Li Yu2, #, Lin Chen1, #, Qi-Xin Hu1, Meng Chen2, Nan Cao2, Chen Zhao1, Chen-Yu Wang1, Cheng-Wei Huang1, Lian-Yun Li1, Mei Ye2,*, Min Wu1,* 1 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Intestinal and Colorectal Diseases, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China 2Division of Gastroenterology, Department of Geriatrics, Hubei Clinical Centre & Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430072, China #Equal contribution to the study. Contact information *Correspondence should be addressed to Dr. Min Wu, Email: [email protected], Tel: 86-27-68756620, or Dr.
    [Show full text]
  • TMEM9 CRISPR/Cas9 KO Plasmid (M): Sc-425907
    SANTA CRUZ BIOTECHNOLOGY, INC. TMEM9 CRISPR/Cas9 KO Plasmid (m): sc-425907 BACKGROUND APPLICATIONS The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and TMEM9 CRISPR/Cas9 KO Plasmid (m) is recommended for the disruption of CRISPR-associated protein (Cas9) system is an adaptive immune response gene expression in mouse cells. defense mechanism used by archea and bacteria for the degradation of foreign genetic material (4,6). This mechanism can be repurposed for other 20 nt non-coding RNA sequence: guides Cas9 functions, including genomic engineering for mammalian systems, such as to a specific target location in the genomic DNA gene knockout (KO) (1,2,3,5). CRISPR/Cas9 KO Plasmid products enable the U6 promoter: drives gRNA scaffold: helps Cas9 identification and cleavage of specific genes by utilizing guide RNA (gRNA) expression of gRNA bind to target DNA sequences derived from the Genome-scale CRISPR Knock-Out (GeCKO) v2 library developed in the Zhang Laboratory at the Broad Institute (3,5). Termination signal Green Fluorescent Protein: to visually REFERENCES verify transfection CRISPR/Cas9 Knockout Plasmid CBh (chicken β-Actin 1. Cong, L., et al. 2013. Multiplex genome engineering using CRISPR/Cas hybrid) promoter: drives systems. Science 339: 819-823. 2A peptide: expression of Cas9 allows production of both Cas9 and GFP from the 2. Mali, P., et al. 2013. RNA-guided human genome engineering via Cas9. same CBh promoter Science 339: 823-826. Nuclear localization signal 3. Ran, F.A., et al. 2013. Genome engineering using the CRISPR-Cas9 system. Nuclear localization signal SpCas9 ribonuclease Nat. Protoc. 8: 2281-2308.
    [Show full text]
  • Recognition of Histone Acetylation by the GAS41 YEATS Domain Promotes H2A.Z Deposition in Non-Small Cell Lung Cancer
    Downloaded from genesdev.cshlp.org on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer Chih-Chao Hsu,1,2,8 Jiejun Shi,3,8 Chao Yuan,1,2,7,8 Dan Zhao,4,5,8 Shiming Jiang,1,2 Jie Lyu,3 Xiaolu Wang,1,2 Haitao Li,4,5 Hong Wen,1,2 Wei Li,3 and Xiaobing Shi1,2,6 1Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 2Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 3Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; 4MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; 5Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China; 6Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas 77030, USA Histone acetylation is associated with active transcription in eukaryotic cells. It helps to open up the chromatin by neutralizing the positive charge of histone lysine residues and providing binding platforms for “reader” proteins. The bromodomain (BRD) has long been thought to be the sole protein module that recognizes acetylated histones. Re- cently, we identified the YEATS domain of AF9 (ALL1 fused gene from chromosome 9) as a novel acetyl-lysine- binding module and showed that the ENL (eleven-nineteen leukemia) YEATS domain is an essential acetyl-histone reader in acute myeloid leukemias.
    [Show full text]
  • Comparison of Methylation Capture Sequencing and Infinium Methylationepic Array in Peripheral Blood Mononuclear Cells
    Shu et al. Epigenetics & Chromatin (2020) 13:51 https://doi.org/10.1186/s13072-020-00372-6 Epigenetics & Chromatin RESEARCH Open Access Comparison of methylation capture sequencing and Infnium MethylationEPIC array in peripheral blood mononuclear cells Chang Shu1,2, Xinyu Zhang1,2, Bradley E. Aouizerat3,4 and Ke Xu1,2* Abstract Background: Epigenome-wide association studies (EWAS) have been widely applied to identify methylation CpG sites associated with human disease. To date, the Infnium MethylationEPIC array (EPIC) is commonly used for high- throughput DNA methylation profling. However, the EPIC array covers only 30% of the human methylome. Methyla- tion Capture bisulfte sequencing (MC-seq) captures target regions of methylome and has advantages of extensive coverage in the methylome at an afordable price. Methods: Epigenome-wide DNA methylation in four peripheral blood mononuclear cell samples was profled by using SureSelectXT Methyl-Seq for MC-seq and EPIC platforms separately. CpG site-based reproducibility of MC-seq was assessed with DNA sample inputs ranging in quantity of high (> 1000 ng), medium (300–1000 ng), and low (150 ng–300 ng). To compare the performance of MC-seq and the EPIC arrays, we conducted a Pearson correlation and methylation value diference at each CpG site that was detected by both MC-seq and EPIC. We compared the percentage and counts in each CpG island and gene annotation between MC-seq and the EPIC array. Results: After quality control, an average of 3,708,550 CpG sites per sample were detected by MC-seq with DNA quantity > 1000 ng. Reproducibility of DNA methylation in MC-seq-detected CpG sites was high among samples with high, medium, and low DNA inputs (r > 0.96).
    [Show full text]
  • H3K27 Acetylation and Gene Expression Analysis Reveals Differences in Placental Chromatin Activity in Fetal Growth Restriction N
    Paauw et al. Clinical Epigenetics (2018) 10:85 https://doi.org/10.1186/s13148-018-0508-x RESEARCH Open Access H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction N. D. Paauw1,6*, A. T. Lely1, J. A. Joles2, A. Franx1, P. G. Nikkels3, M. Mokry4 and B. B. van Rijn1,5,6* Abstract Background: Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP- seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results: Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions.
    [Show full text]
  • Structural and Functional Characterization of the N-Terminal Acetyltransferase Natc
    Structural and functional characterization of the N-terminal acetyltransferase NatC Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry, Pharmacy of Freie Universität Berlin by Stephan Grunwald Berlin October 01, 2019 Die vorliegende Arbeit wurde von April 2014 bis Oktober 2019 am Max-Delbrück-Centrum für Molekulare Medizin unter der Anleitung von PROF. DR. OLIVER DAUMKE angefertigt. Erster Gutachter: PROF. DR. OLIVER DAUMKE Zweite Gutachterin: PROF. DR. ANNETTE SCHÜRMANN Disputation am 26. November 2019 iii iv Erklärung Ich versichere, dass ich die von mir vorgelegte Dissertation selbstständig angefertigt, die benutzten Quellen und Hilfsmittel vollständig angegeben und die Stellen der Arbeit – einschließlich Tabellen, Karten und Abbildungen – die anderen Werken im Wortlaut oder dem Sinn nach entnommen sind, in jedem Einzelfall als Entlehnung kenntlich gemacht habe; und dass diese Dissertation keiner anderen Fakultät oder Universität zur Prüfung vorgelegen hat. Berlin, 9. November 2020 Stephan Grunwald v vi Acknowledgement I would like to thank Prof. Oliver Daumke for giving me the opportunity to do the research for this project in his laboratory and for the supervision of this thesis. I would also like to thank Prof. Dr. Annette Schürmann from the German Institute of Human Nutrition (DifE) in Potsdam-Rehbruecke for being my second supervisor. From the Daumke laboratory I would like to especially thank Dr. Manuel Hessenberger, Dr. Stephen Marino and Dr. Tobias Bock-Bierbaum, who gave me helpful advice. I also like to thank the rest of the lab members for helpful discussions. I deeply thank my wife Theresa Grunwald, who always had some helpful suggestions and kept me alive while writing this thesis.
    [Show full text]
  • Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants
    Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:40050098 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants A dissertation presented by Seav Huong Ly to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts April 2018 © 2018 Seav Huong Ly All rights reserved. Dissertation Advisor: William C. Hahn Seav Huong Ly Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants Abstract The importance of oncogenic KRAS in human cancers have prompted intense efforts to target KRAS and its effectors. To anticipate the development of resistance to these strategies, we previously performed a genome-scale expression screen to identify genes that bypass KRAS oncogenic dependency. Here we test thirty-seven genes that scored over five standard deviations and find that overexpression of LIM homeobox 9 (LHX9), a transcription factor involved in embryonic development, robustly rescues the suppression of KRAS in vitro and xenograft models. Furthermore, LHX9 substantially decreases cell sensitivity to KRASG12C and MEK1/2 inhibitors in KRAS-dependent cells.
    [Show full text]
  • Dynamics of Transcription-Dependent H3k36me3 Marking by the SETD2:IWS1:SPT6 Ternary Complex
    bioRxiv preprint doi: https://doi.org/10.1101/636084; this version posted May 14, 2019. 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. Dynamics of transcription-dependent H3K36me3 marking by the SETD2:IWS1:SPT6 ternary complex Katerina Cermakova1, Eric A. Smith1, Vaclav Veverka2, H. Courtney Hodges1,3,4,* 1 Department of Molecular & Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA 2 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic 3 Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA 4 Department of Bioengineering, Rice University, Houston, TX, 77005, USA * Lead contact; Correspondence to: [email protected] Abstract The genome-wide distribution of H3K36me3 is maintained SETD2 contributes to gene expression by marking gene through various mechanisms. In human cells, H3K36 is bodies with H3K36me3, which is thought to assist in the mono- and di-methylated by eight distinct histone concentration of transcription machinery at the small portion methyltransferases; however, the predominant writer of the of the coding genome. Despite extensive genome-wide data trimethyl mark on H3K36 is SETD21,11,12. Interestingly, revealing the precise localization of H3K36me3 over gene SETD2 is a major tumor suppressor in clear cell renal cell bodies, the physical basis for the accumulation, carcinoma13, breast cancer14, bladder cancer15, and acute maintenance, and sharp borders of H3K36me3 over these lymphoblastic leukemias16–18. In these settings, mutations sites remains rudimentary.
    [Show full text]
  • EZH2 in Normal Hematopoiesis and Hematological Malignancies
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 3 EZH2 in normal hematopoiesis and hematological malignancies Laurie Herviou2, Giacomo Cavalli2, Guillaume Cartron3,4, Bernard Klein1,2,3 and Jérôme Moreaux1,2,3 1 Department of Biological Hematology, CHU Montpellier, Montpellier, France 2 Institute of Human Genetics, CNRS UPR1142, Montpellier, France 3 University of Montpellier 1, UFR de Médecine, Montpellier, France 4 Department of Clinical Hematology, CHU Montpellier, Montpellier, France Correspondence to: Jérôme Moreaux, email: [email protected] Keywords: hematological malignancies, EZH2, Polycomb complex, therapeutic target Received: August 07, 2015 Accepted: October 14, 2015 Published: October 20, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies. PHYSIOLOGICAL FUNCTIONS OF EZH2 state through tri-methylation of lysine 27 on histone H3 (H3K27me3) [6].
    [Show full text]
  • Oncogenic Deregulation of EZH2 As an Opportunity for Targeted Therapy in Lung Cancer
    Published OnlineFirst June 16, 2016; DOI: 10.1158/2159-8290.CD-16-0164 RESEARCH ARTICLE Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer Haikuo Zhang1,2, Jun Qi1,2, Jaime M. Reyes1, Lewyn Li3, Prakash K. Rao3, Fugen Li3, Charles Y. Lin1, Jennifer A. Perry1, Matthew A. Lawlor1, Alexander Federation1, Thomas De Raedt2,4, Yvonne Y. Li1,2, Yan Liu1,2, Melissa A. Duarte3, Yanxi Zhang1,2, Grit S. Herter-Sprie1,2, Eiki Kikuchi1,2, Julian Carretero5, Charles M. Perou6, Jacob B. Reibel1,2, Joshiawa Paulk1, Roderick T. Bronson7, Hideo Watanabe1,2, Christine Fillmore Brainson8,9,10, Carla F. Kim8,9,10, Peter S. Hammerman1,2, Myles Brown2,3, Karen Cichowski2,4, Henry Long3, James E. Bradner1,2, and Kwok-Kin Wong1,2,11 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst June 16, 2016; DOI: 10.1158/2159-8290.CD-16-0164 ABSTRACT As a master regulator of chromatin function, the lysine methyltransferase EZH2 orchestrates transcriptional silencing of developmental gene networks. Overex- pression of EZH2 is commonly observed in human epithelial cancers, such as non–small cell lung carci- noma (NSCLC), yet definitive demonstration of malignant transformation by deregulatedEZH2 remains elusive. Here, we demonstrate the causal role of EZH2 overexpression in NSCLC with new genetically engineered mouse models of lung adenocarcinoma. Deregulated EZH2 silences normal developmental pathways, leading to epigenetic transformation independent of canonical growth factor pathway acti- vation. As such, tumors feature a transcriptional program distinct from KRAS- and EGFR-mutant mouse lung cancers, but shared with human lung adenocarcinomas exhibiting high EZH2 expression.
    [Show full text]
  • Supplementary Table 2 Targets Description Uniprot NM 001001182 Bromodomain Adjacent to Zinc Finger Domain, 2B Q8CFP4 NM 001001309 Integrin Alpha 8 (Itga8), Mrna
    Supplementary Table 2 targets description UniProt NM_001001182 bromodomain adjacent to zinc finger domain, 2B Q8CFP4 NM_001001309 integrin alpha 8 (Itga8), mRNA. A2ARA8 NM_001001321 solute carrier family 35, member D2 (Slc35d2), mRNA. Q762D5 NM_001003920 BR serine/threonine kinase 1 (Brsk1), mRNA. Q5RJI5 NM_001004468 transforming, acidic coiled-coil containing protein 2 Q9JJG0 NM_001005508 Rho GTPase activating protein 30 (Arhgap30), mRNA. Q640N3 NM_001008785 kelch repeat and BTB (POZ) domain containing 8 Q3UQV5 NM_001013022 outer dense fiber of sperm tails 3B (Odf3b), mRNA. Q5M8M2 NM_001013609 testis expressed gene 24 (Tex24), mRNA. Q5DP50 NM_001015681 RIKEN cDNA E130308A19 gene (E130308A19Rik), transcript Q8C4P0 NM_001017426 KDM1 lysine (K)-specific demethylase 6B (Kdm6b), mRNA. Q8K0Z1 NM_001024945 quiescin Q6 sulfhydryl oxidase 1 (Qsox1), transcript Q8BND5 NM_001025296 DNA fragmentation factor, alpha subunit (Dffa), Q8CA98 NM_001029983 mannosidase, alpha, class 1B, member 1 (Man1b1), mRNA. Q923C1 NM_001033269 eukaryotic translation initiation factor 4E family - NM_001033536 regulatory factor X, 7 (Rfx7), mRNA. Q8CB07 NM_001034037 RIKEN cDNA 1700024G13 gene (1700024G13Rik), mRNA. - NM_001034863 transmembrane protein 136 (Tmem136), mRNA. Q3TYE7 NM_001039088 SEH1-like (S. cerevisiae (Seh1l), transcript variant Q8R2U0 NM_001039644 ER degradation enhancer, mannosidase alpha-like 3 Q8R1X5 NM_001042592 arrestin domain containing 4 (Arrdc4), transcript Q9D6S6 NM_001045536 zinc finger, ZZ-type with EF hand domain 1 (Zzef1), Q5SSH7 NM_001081048 solute carrier family 25 (mitochondrial carrier), Q9DB41 NM_001081088 low density lipoprotein receptor-related protein 2 Q3V346 NM_001081152 nuclear protein in the AT region (Npat), mRNA. Q8BPV1 NM_001081205 NIPA-like domain containing 1 (Nipal1), mRNA. Q8BMW7 NM_001081206 diacylglycerol kinase, iota (Dgki), mRNA. - NM_001081366 vacuolar protein sorting 8 homolog (S. cerevisiae) Q8CIG5 NM_001081417 chromodomain helicase DNA binding protein 7 (Chd7), A2AJK6 NM_001081433 ankyrin repeat domain 44 (Ankrd44), mRNA.
    [Show full text]