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Open Dogan Phdthesis Final.Pdf
The Pennsylvania State University The Graduate School Eberly College of Science ELUCIDATING BIOLOGICAL FUNCTION OF GENOMIC DNA WITH ROBUST SIGNALS OF BIOCHEMICAL ACTIVITY: INTEGRATIVE GENOME-WIDE STUDIES OF ENHANCERS A Dissertation in Biochemistry, Microbiology and Molecular Biology by Nergiz Dogan © 2014 Nergiz Dogan Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2014 ii The dissertation of Nergiz Dogan was reviewed and approved* by the following: Ross C. Hardison T. Ming Chu Professor of Biochemistry and Molecular Biology Dissertation Advisor Chair of Committee David S. Gilmour Professor of Molecular and Cell Biology Anton Nekrutenko Professor of Biochemistry and Molecular Biology Robert F. Paulson Professor of Veterinary and Biomedical Sciences Philip Reno Assistant Professor of Antropology Scott B. Selleck Professor and Head of the Department of Biochemistry and Molecular Biology *Signatures are on file in the Graduate School iii ABSTRACT Genome-wide measurements of epigenetic features such as histone modifications, occupancy by transcription factors and coactivators provide the opportunity to understand more globally how genes are regulated. While much effort is being put into integrating the marks from various combinations of features, the contribution of each feature to accuracy of enhancer prediction is not known. We began with predictions of 4,915 candidate erythroid enhancers based on genomic occupancy by TAL1, a key hematopoietic transcription factor that is strongly associated with gene induction in erythroid cells. Seventy of these DNA segments occupied by TAL1 (TAL1 OSs) were tested by transient transfections of cultured hematopoietic cells, and 56% of these were active as enhancers. Sixty-six TAL1 OSs were evaluated in transgenic mouse embryos, and 65% of these were active enhancers in various tissues. -
Renal Cell Neoplasms Contain Shared Tumor Type–Specific Copy Number Variations
The American Journal of Pathology, Vol. 180, No. 6, June 2012 Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2012.01.044 Tumorigenesis and Neoplastic Progression Renal Cell Neoplasms Contain Shared Tumor Type–Specific Copy Number Variations John M. Krill-Burger,* Maureen A. Lyons,*† The annual incidence of renal cell carcinoma (RCC) has Lori A. Kelly,*† Christin M. Sciulli,*† increased steadily in the United States for the past three Patricia Petrosko,*† Uma R. Chandran,†‡ decades, with approximately 58,000 new cases diag- 1,2 Michael D. Kubal,§ Sheldon I. Bastacky,*† nosed in 2010, representing 3% of all malignancies. Anil V. Parwani,*†‡ Rajiv Dhir,*†‡ and Treatment of RCC is complicated by the fact that it is not a single disease but composes multiple tumor types with William A. LaFramboise*†‡ different morphological characteristics, clinical courses, From the Departments of Pathology* and Biomedical and outcomes (ie, clear-cell carcinoma, 82% of RCC ‡ Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania; cases; type 1 or 2 papillary tumors, 11% of RCC cases; † the University of Pittsburgh Cancer Institute, Pittsburgh, chromophobe tumors, 5% of RCC cases; and collecting § Pennsylvania; and Life Technologies, Carlsbad, California duct carcinoma, approximately 1% of RCC cases).2,3 Benign renal neoplasms are subdivided into papillary adenoma, renal oncocytoma, and metanephric ade- Copy number variant (CNV) analysis was performed on noma.2,3 Treatment of RCC often involves surgical resec- renal cell carcinoma (RCC) specimens (chromophobe, tion of a large renal tissue component or removal of the clear cell, oncocytoma, papillary type 1, and papillary entire affected kidney because of the relatively large size of type 2) using high-resolution arrays (1.85 million renal tumors on discovery and the availability of a life-sus- probes). -
A Private 16Q24.2Q24.3 Microduplication in a Boy with Intellectual Disability, Speech Delay and Mild Dysmorphic Features
G C A T T A C G G C A T genes Article A Private 16q24.2q24.3 Microduplication in a Boy with Intellectual Disability, Speech Delay and Mild Dysmorphic Features Orazio Palumbo * , Pietro Palumbo , Ester Di Muro, Luigia Cinque, Antonio Petracca, Massimo Carella and Marco Castori Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy; [email protected] (P.P.); [email protected] (E.D.M.); [email protected] (L.C.); [email protected] (A.P.); [email protected] (M.C.); [email protected] (M.C.) * Correspondence: [email protected]; Tel.: +39-088-241-6350 Received: 5 June 2020; Accepted: 24 June 2020; Published: 26 June 2020 Abstract: No data on interstitial microduplications of the 16q24.2q24.3 chromosome region are available in the medical literature and remain extraordinarily rare in public databases. Here, we describe a boy with a de novo 16q24.2q24.3 microduplication at the Single Nucleotide Polymorphism (SNP)-array analysis spanning ~2.2 Mb and encompassing 38 genes. The patient showed mild-to-moderate intellectual disability, speech delay and mild dysmorphic features. In DECIPHER, we found six individuals carrying a “pure” overlapping microduplication. Although available data are very limited, genomic and phenotype comparison of our and previously annotated patients suggested a potential clinical relevance for 16q24.2q24.3 microduplication with a variable and not (yet) recognizable phenotype predominantly affecting cognition. Comparing the cytogenomic data of available individuals allowed us to delineate the smallest region of overlap involving 14 genes. Accordingly, we propose ANKRD11, CDH15, and CTU2 as candidate genes for explaining the related neurodevelopmental manifestations shared by these patients. -
Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) Beyond SMARCA4 Mutations: a Comprehensive Genomic Analysis
cells Article Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis Aurélie Auguste 1,Félix Blanc-Durand 2 , Marc Deloger 3 , Audrey Le Formal 1, Rohan Bareja 4,5, David C. Wilkes 4 , Catherine Richon 6,Béatrice Brunn 2, Olivier Caron 6, Mojgan Devouassoux-Shisheboran 7,Sébastien Gouy 2, Philippe Morice 2, Enrica Bentivegna 2, Andrea Sboner 4,5,8, Olivier Elemento 4,8, Mark A. Rubin 9 , Patricia Pautier 2, Catherine Genestie 10, Joanna Cyrta 4,9,11 and Alexandra Leary 1,2,* 1 Medical Oncologist, Gynecology Unit, Lead Translational Research Team, INSERM U981, Gustave Roussy, 94805 Villejuif, France; [email protected] (A.A.); [email protected] (A.L.F.) 2 Gynecological Unit, Department of Medicine, Gustave Roussy, 94805 Villejuif, France; [email protected] (F.B.-D.); [email protected] (B.B.); [email protected] (S.G.); [email protected] (P.M.); [email protected] (E.B.); [email protected] (P.P.) 3 Bioinformatics Core Facility, Gustave Roussy Cancer Center, UMS CNRS 3655/INSERM 23 AMMICA, 94805 Villejuif, France; [email protected] 4 Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10001, USA; [email protected] (R.B.); [email protected] (D.C.W.); [email protected] (A.S.); [email protected] (O.E.); [email protected] (J.C.) 5 Institute for Computational Biomedicine, Weill Cornell -
(HABP4): a Candidate Tumor Suppressor in Colorectal Cancer
www.oncotarget.com Oncotarget, 2020, Vol. 11, (No. 46), pp: 4325-4337 Research Paper Intracellular hyaluronic acid-binding protein 4 (HABP4): a candidate tumor suppressor in colorectal cancer Talita Diniz Melo-Hanchuk2,*, Carolina Colleti1,*, Ângela Saito3,*, Maria Carolina Santos Mendes4, José Barreto Campello Carvalheira4, Jose Vassallo5 and Jörg Kobarg1 1School of Pharmaceutical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil 2Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, SP, Brazil 3Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, SP, Brazil 4Division of Oncology, Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil 5Laboratory of Investigative Pathology, CIPED, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil *These authors contributed equally to this work Correspondence to: Jörg Kobarg, email: [email protected] Keywords: colon cancer; regulatory protein; gene knockout; proliferation; tumor marker Received: September 08, 2020 Accepted: October 27, 2020 Published: November 17, 2020 Copyright: © 2020 Melo-Hanchuk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Hyaluronic Acid-binding protein 4 (HABP4) is a regulatory protein of 57 kDa that is functionally involved in transcription regulation and RNA metabolism and shows several characteristics common to oncoproteins or tumor suppressors, including altered expression in cancer tissues, nucleus/cytoplasm shuttling, intrinsic lack of protein structure, complex interactomes and post translational modifications. -
Role of Transfer RNA Modification and Aminoacylation in the Etiology of Congenital Intellectual Disability
Franz et al. J Transl Genet Genom 2020;4:50-70 Journal of Translational DOI: 10.20517/jtgg.2020.13 Genetics and Genomics Review Open Access Role of transfer RNA modification and aminoacylation in the etiology of congenital intellectual disability Martin Franz#, Lisa Hagenau#, Lars R. Jensen, Andreas W. Kuss Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald 17475, Germany. #Authors cotributed equally. Correspondence to: Prof. Andreas W. Kuss; Dr. Lars R. Jensen, Department of Functional Genomics, University Medicine Greifswald, C_FunGene, Felix-Hausdorff-Str. 8, Greifswald 17475, Germany. E-mail: [email protected]; [email protected] How to cite this article: Franz M, Hagenau L, Jensen LR, Kuss AW. Role of transfer RNA modification and aminoacylation in the etiology of congenital intellectual disability. J Transl Genet Genom 2020;4:50-70. http://dx.doi.org/10.20517/jtgg.2020.13 Received: 14 Feb 2020 First Decision: 17 Mar 2020 Revised: 30 Mar 2020 Accepted: 23 Apr 2020 Available online: 16 May 2020 Science Editor: Tjitske Kleefstra Copy Editor: Jing-Wen Zhang Production Editor: Tian Zhang Abstract Transfer RNA (tRNA) modification and aminoacylation are post-transcriptional processes that play a crucial role in the function of tRNA and thus represent critical steps in gene expression. Knowledge of the exact processes and effects of the defects in various tRNAs remains incomplete, but a rapidly increasing number of publications over the last decade has shown a growing amount of evidence as to the importance of tRNAs for normal human development, including brain formation and the development and maintenance of higher cognitive functions as well. -
Comparative Transcriptome Profiling of the Human and Mouse Dorsal Root Ganglia: an RNA-Seq-Based Resource for Pain and Sensory Neuroscience Research
bioRxiv preprint doi: https://doi.org/10.1101/165431; this version posted October 13, 2017. 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. Title: Comparative transcriptome profiling of the human and mouse dorsal root ganglia: An RNA-seq-based resource for pain and sensory neuroscience research Short Title: Human and mouse DRG comparative transcriptomics Pradipta Ray 1, 2 #, Andrew Torck 1 , Lilyana Quigley 1, Andi Wangzhou 1, Matthew Neiman 1, Chandranshu Rao 1, Tiffany Lam 1, Ji-Young Kim 1, Tae Hoon Kim 2, Michael Q. Zhang 2, Gregory Dussor 1 and Theodore J. Price 1, # 1 The University of Texas at Dallas, School of Behavioral and Brain Sciences 2 The University of Texas at Dallas, Department of Biological Sciences # Corresponding authors Theodore J Price Pradipta Ray School of Behavioral and Brain Sciences School of Behavioral and Brain Sciences The University of Texas at Dallas The University of Texas at Dallas BSB 14.102G BSB 10.608 800 W Campbell Rd 800 W Campbell Rd Richardson TX 75080 Richardson TX 75080 972-883-4311 972-883-7262 [email protected] [email protected] Number of pages: 27 Number of figures: 9 Number of tables: 8 Supplementary Figures: 4 Supplementary Files: 6 Word count: Abstract = 219; Introduction = 457; Discussion = 1094 Conflict of interest: The authors declare no conflicts of interest Patient anonymity and informed consent: Informed consent for human tissue sources were obtained by Anabios, Inc. (San Diego, CA). Human studies: This work was approved by The University of Texas at Dallas Institutional Review Board (MR 15-237). -
Urm1 in Trna Thiolation and Protein Modification
Urm1 in tRNA thiolation and protein modification Annemarthe G. van der Veen Urm1 in tRNA thiolation and protein modification A.G. van der Veen Thesis, Utrecht University, The Netherlands A.G. van der Veen 2011 ISBN: 9789461081728 Cover image: Stata Center, MIT campus. Photo courtesy of W. van der Veen Invitation: Image courtesy of Eugene Galleries, Boston Printed by: Gildeprint Drukkerijen, Enschede Urm1 in tRNA thiolation and protein modification Urm1 in tRNA thiolatie en eiwit modificatie (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op maandag 30 mei 2011 des middags te 12.45 uur door Annemarthe Godelieve van der Veen geboren op 13 september 1982 te Hardenberg Promotoren: Prof.dr. H.L. Ploegh Prof.dr. E.J.H.J. Wiertz The research described in this thesis was supported by a pre-doctoral grant from the Boehringer Ingelheim Fonds. Voor papa en mama Contents Chapter 1 General introduction 8 Chapter 2 A functional proteomics approach links the Ubiquitin- 28 related modifier Urm1 to a tRNA modification pathway Chapter 3 Role of the Ubiquitin-like molecule Urm1 as a 46 noncanonical lysine-directed protein modifier Chapter 4 Transgenic mice expressing a dominant negative Urm1 74 mutant fail to generate offspring Chapter 5 Urm1B, an alternate isoform of Urm1, is stabilized and 90 redistributed by its interaction with ATPBD3 Chapter 6 General discussion 102 English summary 114 Nederlandse samenvatting 116 Acknowledgements 118 Curriculum vitae 121 List of publications 122 Chapter 1 General introduction Post-translational modifications Cellular homeostasis requires tight control of protein activity, function, stability, and localization. -
Chromosomal Microarray Analysis in Turkish Patients with Unexplained Developmental Delay and Intellectual Developmental Disorders
177 Arch Neuropsychitry 2020;57:177−191 RESEARCH ARTICLE https://doi.org/10.29399/npa.24890 Chromosomal Microarray Analysis in Turkish Patients with Unexplained Developmental Delay and Intellectual Developmental Disorders Hakan GÜRKAN1 , Emine İkbal ATLI1 , Engin ATLI1 , Leyla BOZATLI2 , Mengühan ARAZ ALTAY2 , Sinem YALÇINTEPE1 , Yasemin ÖZEN1 , Damla EKER1 , Çisem AKURUT1 , Selma DEMİR1 , Işık GÖRKER2 1Faculty of Medicine, Department of Medical Genetics, Edirne, Trakya University, Edirne, Turkey 2Faculty of Medicine, Department of Child and Adolescent Psychiatry, Trakya University, Edirne, Turkey ABSTRACT Introduction: Aneuploids, copy number variations (CNVs), and single in 39 (39/123=31.7%) patients. Twelve CNV variant of unknown nucleotide variants in specific genes are the main genetic causes of significance (VUS) (9.75%) patients and 7 CNV benign (5.69%) patients developmental delay (DD) and intellectual disability disorder (IDD). were reported. In 6 patients, one or more pathogenic CNVs were These genetic changes can be detected using chromosome analysis, determined. Therefore, the diagnostic efficiency of CMA was found to chromosomal microarray (CMA), and next-generation DNA sequencing be 31.7% (39/123). techniques. Therefore; In this study, we aimed to investigate the Conclusion: Today, genetic analysis is still not part of the routine in the importance of CMA in determining the genomic etiology of unexplained evaluation of IDD patients who present to psychiatry clinics. A genetic DD and IDD in 123 patients. diagnosis from CMA can eliminate genetic question marks and thus Method: For 123 patients, chromosome analysis, DNA fragment analysis alter the clinical management of patients. Approximately one-third and microarray were performed. Conventional G-band karyotype of the positive CMA findings are clinically intervenable. -
Whole-Exome Sequencing Identifies Causative Mutations in Families
BASIC RESEARCH www.jasn.org Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract Amelie T. van der Ven,1 Dervla M. Connaughton,1 Hadas Ityel,1 Nina Mann,1 Makiko Nakayama,1 Jing Chen,1 Asaf Vivante,1 Daw-yang Hwang,1 Julian Schulz,1 Daniela A. Braun,1 Johanna Magdalena Schmidt,1 David Schapiro,1 Ronen Schneider,1 Jillian K. Warejko,1 Ankana Daga,1 Amar J. Majmundar,1 Weizhen Tan,1 Tilman Jobst-Schwan,1 Tobias Hermle,1 Eugen Widmeier,1 Shazia Ashraf,1 Ali Amar,1 Charlotte A. Hoogstraaten,1 Hannah Hugo,1 Thomas M. Kitzler,1 Franziska Kause,1 Caroline M. Kolvenbach,1 Rufeng Dai,1 Leslie Spaneas,1 Kassaundra Amann,1 Deborah R. Stein,1 Michelle A. Baum,1 Michael J.G. Somers,1 Nancy M. Rodig,1 Michael A. Ferguson,1 Avram Z. Traum,1 Ghaleb H. Daouk,1 Radovan Bogdanovic,2 Natasa Stajic,2 Neveen A. Soliman,3,4 Jameela A. Kari,5,6 Sherif El Desoky,5,6 Hanan M. Fathy,7 Danko Milosevic,8 Muna Al-Saffar,1,9 Hazem S. Awad,10 Loai A. Eid,10 Aravind Selvin,11 Prabha Senguttuvan,12 Simone Sanna-Cherchi,13 Heidi L. Rehm,14 Daniel G. MacArthur,14,15 Monkol Lek,14,15 Kristen M. Laricchia,15 Michael W. Wilson,15 Shrikant M. Mane,16 Richard P. Lifton,16,17 Richard S. Lee,18 Stuart B. Bauer,18 Weining Lu,19 Heiko M. Reutter ,20,21 Velibor Tasic,22 Shirlee Shril,1 and Friedhelm Hildebrandt1 Due to the number of contributing authors, the affiliations are listed at the end of this article. -
Drosophila Melanogaster Y Chromosome Genes Affect Male Sensitivity to Microbial Infections
insects Article Drosophila melanogaster Y Chromosome Genes Affect Male Sensitivity to Microbial Infections Gloria Bartolo, Leandra O. Gonzalez , Anastasia Levitin and Mikhail Martchenko Shilman * Henry E. Riggs School of Applied Life Sciences, Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711, USA; [email protected] (G.B.); [email protected] (L.O.G.); [email protected] (A.L.) * Correspondence: [email protected] Simple Summary: This manuscript focuses on the protein-encoding genes of the Drosophila melanogaster Y chromosome and their role in immunity. Since their discovery, these genes have mainly been studied for their role(s) in male fertility, such as spermatogenesis. Two previously published papers have linked the polymorphism within the Y chromosome and immunity. Currently, there is no research article to our knowledge that has studied the effect of the individual genes of the Y chromosome on fly immunity. Here, we aim to address the lack of immunity-related knowledge of Y chromosome genes by determining the effect of many of these genes on male sensitivity to microbial infections. We challenged loss-of-function gene mutants with bacterial and fungal pathogens orally and observed any significant fly survival changes. We discovered several genes affecting male sensitivity to both bacterial and fungal infections. While most of the Y chromosome genes were found to reduce sensitivity, we found one gene increases sensitivity to fungal infection. Because several genes were found to increase male sensitivity to microbial infections, inhibitors for such genes could be introduced in areas where fruit flies are pests. Amid declining bee populations, Diptera pollinators could be protected from fungal infections with Y-gene inhibitors. -
Characterizing Rare and Low-Frequency Height-Associated
There are amendments to this paper ARTICLE https://doi.org/10.1038/s41467-019-12276-5 OPEN Characterizing rare and low-frequency height- associated variants in the Japanese population Masato Akiyama et al.# Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel (N = 1234567890():,; 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Fur- thermore, a gene-based analysis identifies two genes with multiple height-increasing rare and −6 low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; PSKAT-O < 2.5 × 10 ). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations. Correspondence and requests for materials should be addressed to Y.K. (email: [email protected]). #A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2019)10:4393 | https://doi.org/10.1038/s41467-019-12276-5 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-12276-5 uman height is a highly heritable trait under polygenic independent loci, including nine novel loci with genome-wide Hinheritance1.