DOCSLIB.ORG

Functional Characterization of the TRRAP Pseudokinase and Its Chaperone TTT During Transcriptional Regulation in Colorectal Cancer Dylane Detilleux

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Functional characterization of the TRRAP pseudokinase and its chaperone TTT during transcriptional regulation in colorectal cancer Dylane Detilleux To cite this version: Dylane Detilleux. Functional characterization of the TRRAP pseudokinase and its chaperone TTT during transcriptional regulation in colorectal cancer. Agricultural sciences. Université Montpellier, 2018. English. NNT : 2018MONTT092. tel-02056668 HAL Id: tel-02056668 https://tel.archives-ouvertes.fr/tel-02056668 Submitted on 4 Mar 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE MONTPELLIER En Biochimie et Biologie moléculaire École doctorale CBS2 n°168 – Sciences Chimiques et Biologiques pour la Santé Unité de recherche UMR 5237 – Centre de Recherche en Biologie cellulaire de Montpellier Functional characterization of the TRRAP pseudokinase and its chaperone TTT during transcriptional regulation in colorectal cancer. ! Présentée par Dylane DETILLEUX Le 30 Novembre 2018 Sous la direction de Dominique HELMLINGER Et Bérengère PRADET-BALADE Devant le jury composé de Dominique HELMLINGER, CRCE, CRBM Directeur Bérengère PRADET-BALADE, CRCE, CRBM Co-Directeur László TORA, DRCE1, IGBMC Rapporteur Martin EILERS, Professeur, Université de Würzburg Rapporteur Anne-Marie MARTINEZ, Professeur, IGH Présidente Didier TROUCHE, DR1, LBCMCP Examinateur ! ! "#),-4()"%),),1.! ! First and foremost, I would like to thank Dr Lázló TORA, Professor Martin EILERS, Professor Anne- Marie MARTINEZ and Dr Didier TROUCHE for accepting to be a member of the jury and for taking the time to read and evaluate my thesis work. Je tiens ensuite à exprimer toute ma reconnaissance à mon chef Dom HELMLINGER. Je n’aurais pu espérer meilleur directeur de thèse. Merci de m’avoir transmis la passion dès mon arrivée au sein de l’équipe, parmi la team S. pombe . Merci pour ton encadrement, ton soutien, ton aide, ton écoute et ta disponibilité au cours de ces 4 années de thèse. Merci aussi pour ton dynamisme communicatif, et surtout merci pour cette confiance que tu m’as accordée. Merci d’avoir cru en moi et mes capacités, et de m’avoir menée ici aujourd’hui. Merci à Bérengère pour m’avoir accompagnée lors de mes débuts avec les cellules humaines. Merci de m’avoir laissé l’autonomie nécessaire tout en apportant tes inputs sur le projet, et merci aussi pour tes relectures. Je remercie bien évidemment les membres de mon équipe, pour leur soutien, leur gentillesse, mais aussi la bonne ambiance qu’ils ont apportée au cours de ces 4 années de montagnes russes. Sans oublier leur tolérance à mon superbe caractère... Je tiens tout particulièrement à remercier Céline, la Wonder-woman de l’équipe, non seulement elle gère le labo à merveille (et attention faut que ça file droit) mais en plus elle assure en tant que maman. En fait Céline c’est un peu notre maman au labo. Merci à toi pour ton écoute, tes conseils et ton relativisme qui m’ont bien souvent été très précieux, merci aussi pour ces bons gâteaux (le brookie c’est une tuerie !), ces instants carrés de chocolat et ces parties de badminton. Merci aux mecs de l’équipe, Alberto et Damien, mais aussi Thomas, sans qui je n’aurais pas autant ri. Merci à Damien, le breton au bon caractère et pas si alcoolique que ça, pour ces fous rires, parfois (souvent) à ton insu j’avoue, spéciale dédicace à tes moments de solitudes où on n’a pas toujours compris tes références. Merci à Alberto, de m’avoir écoutée et rassurée plusieurs fois. J’aurai chaque année une petite pensée pour toi, être nés le même jour fallait le faire ! Ces moments post-repas au café vont quand même sacrément me manquer. Merci à Peggy, de m’avoir soutenue pour ne pas craquer dans ces derniers mois, merci pour ta patate et tes cours d’autodérision. Merci aussi pour ces petits moments commérage, thés et mode. Je remercie bien évidemment Fanny et nos inoubliables moments canapé (dis comme ça c’est un peu suspect), merci d’avoir été là au cours de toutes ces années, en tant que confidente-thérapeute- psychologue-psychiatre mais surtout en tant qu’amie. Merci pour ton écoute (même quand je monopolisais la parole), pour tes conseils, pour tous ces délires et ces moments hors labo aussi. Merci à Laurie, pour tes petits messages de soutien, pour tous ces restos partagés et surtout ton écoute sur les trajets du retour. Encore félicitations à toi Docteur. Je remercie aussi Céline Gongora et Didier Trouche pour leurs encouragements et le suivi sur mon travail, lors de mes comités de thèse. Merci aux personnes de l’institut que je n’ai pas citées mais que je remercie pour leur aide apportée, ou tout simplement leur bonne humeur. Sans oublier ma famille là depuis le tout début de cette folle aventure. Merci de m’avoir aussi bien entourée, encouragée et soutenue, et d’être autant fiers de moi. Merci surtout de m’avoir supportée moi et mon sale caractère, et de continuer à nous supporter (c’est ça la famille, pas le choix !). Merci à Marthe qui fait quasi-partie de la famille. Merci à Paul d’avoir était présent et de s’être toujours plié en quatre pour me faire plaisir (fût une époque je pense que tu devais connaître les rayons de chez Carrefour par cœur). Spéciale dédicace à toi et Yo, mes supers chauffeurs avant que je n’aie le permis. Merci à mes grands-parents, mes beaux- frères, mes nièces et neveux. Merci à vous mes sœurs, je pense particulièrement à Slo et nos moments au café Jo et puis au riche et aussi au Yam’s des fois, au bibal aussi non ? A Momo qui est sans doute celle qui a le mieux compris ce que j’ai enduré pendant ces 4 années. Et puis Lauré, ma grande sœur qui m’a toujours protégée et qui continue de le faire (même si j’approche des 30ans...). Un immense merci à ma maman, de m’avoir permis d’en être là aujourd’hui, merci pour tout ton réconfort et ton soutien. Et puis merci à TOI, merci d’avoir compris à quel point c’était important pour moi. Merci de m’avoir accompagnée lors de ces escapades nocturnes en salle de culture (non le sur-chaussure ça ne se met pas sur la tête). Merci pour ta curiosité portée sur mon travail (une immunoprécipitation c’est quoi, ben imagine un troupeau de mouton, tu attrapes un mouton et après tu regardes avec quels autres moutons il est en contact (il fallait une sacrée imagination pour réussir à comprendre...). Merci d’avoir tenu à lire ma thèse (après avoir piqué plusieurs fois du nez tout de même, tu y es arrivé... à la fin de l’intro). Mais surtout merci d’avoir été mon punching-ball, mon défouloir. Merci d’avoir partagé mes joies et mes tristesses. Merci d’être toi et d’avoir partagé ça avec moi. 1" ()!-0!#-,1),1.! .1,,"23!4,!02),#5!7!2).1,)!),!02",#"4.!777777777777777777777777777777777777777777777!4! " 2)84"14-,.!777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777!9! (4.1!-0!04%12).!777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777!:! (4.1!-0!1" ().!77777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777!;! .2)0"#)!77777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777!A! 4,12-"1#14-,!777777777777777777777777777777777777777777777777777777777777777777777777777777777777777777!99 ! (X ! 1%&4()3(.,!.-! 31),./1(03(.,! (,(3()3(., !XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!aa! RM ! 3C3&'D)3*C5),-D,.*MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMM'RR ! aXaX ! /234!I32E27438!XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!aa ! aXaXaX ! /234!I32E2743!94:7N34W!932E!:!74Q7;22C!=48A3BI7B2C!72!:!E234!:C=!E234!AA:EE4CF4=!OB4PX!XXXXXXXXXXXXXXX!aa ! aXaXbX ! /234!I32E2743!AE:8848W!O:3B:7B2C!BC!7A4!73:C8A3BI7B2C!BCB7B:7B2C!I:7743CXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!ac ! aXbX ! K:8:E!73:C8A3BI7B2C!E:AABC43R!XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!ad ! aXbXaX ! 1,)!I2ERE43:848!XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!ad ! aXbXbX ! /:C2CBA:E!0(/!:884E;ERW!32E48!29!7A4!=B99434C7!&3-8XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!af ! :O ! 3-((PZP,)!BC743:A7B2C!:C=!87:;BEBS:7B2C!;R!3-(()!:C=!3-((K!XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!ag ! ;O ! 3-((-!:C=!02E!((!34A3NB7E4C7XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!ba ! AO ! 3-((%T!3-((U!:C=!I32E2743!P,)!2I4CBCF!XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!bb ! SM ! .D,12&3D,.*'.8'D47'43C3&'D)3*C5),-D,.*'1354,*7)I'MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMM'S8 ! bXaX ! 9,C Z:A7BCF!P,)!4E4E4C78!XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX!bd
Recommended publications
  • Gene Regulation and Speciation in House Mice

    Gene Regulation and Speciation in House Mice

    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research Gene regulation and speciation in house mice Katya L. Mack,1 Polly Campbell,2 and Michael W. Nachman1 1Museum of Vertebrate Zoology and Department of Integrative Biology, University of California, Berkeley, California 94720-3160, USA; 2Department of Integrative Biology, Oklahoma State University, Stillwater, Oklahoma 74078, USA One approach to understanding the process of speciation is to characterize the genetic architecture of post-zygotic isolation. As gene regulation requires interactions between loci, negative epistatic interactions between divergent regulatory elements might underlie hybrid incompatibilities and contribute to reproductive isolation. Here, we take advantage of a cross between house mouse subspecies, where hybrid dysfunction is largely unidirectional, to test several key predictions about regulatory divergence and reproductive isolation. Regulatory divergence between Mus musculus musculus and M. m. domesticus was charac- terized by studying allele-specific expression in fertile hybrid males using mRNA-sequencing of whole testes. We found ex- tensive regulatory divergence between M. m. musculus and M. m. domesticus, largely attributable to cis-regulatory changes. When both cis and trans changes occurred, they were observed in opposition much more often than expected under a neutral model, providing strong evidence of widespread compensatory evolution. We also found evidence for lineage-specific positive se- lection on a subset of genes related to transcriptional regulation. Comparisons of fertile and sterile hybrid males identified a set of genes that were uniquely misexpressed in sterile individuals. Lastly, we discovered a nonrandom association between these genes and genes showing evidence of compensatory evolution, consistent with the idea that regulatory interactions might contribute to Dobzhansky-Muller incompatibilities and be important in speciation.
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    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.
  • Taenia Solium TAF6 and TAF9 Binds to a Putative Downstream Promoter Element

    Taenia Solium TAF6 and TAF9 Binds to a Putative Downstream Promoter Element

    bioRxiv preprint doi: https://doi.org/10.1101/106997; this version posted February 8, 2017. 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. Taenia solium TAF6 and TAF9 binds to a putative Downstream Promoter Element present in TsTBP1 gene core promoter. Oscar Rodríguez-Lima1, #a, Ponciano García-Gutierrez2, Lucía Jimenez1, Angel Zarain-Herzberg3, Roberto Lazarini4 and Abraham Landa1*. 1Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México. Ciudad de México, México. 2Departamento de Química, Universidad Autónoma Metropolitana–Iztapalapa. Ciudad de México, México. 3Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México. Ciudad de México, México. 4Departamento de Biología Experimental, Universidad Autónoma Metropolitana– Iztapalapa. Ciudad de México, México. #a Current address: Center for Integrative Genomics, Lausanne University, Lausanne, Switzerland. *Corresponding author: Abraham Landa, Ph.D. Universidad Nacional Autónoma de México. Departamento de Microbiología y Parasitología, Facultad de Medicina Edificio A 2do piso. Ciudad Universitaria. CDMX 04510, México Phone: (52 55) 56-23-23-57, Fax: (52 55) 56-23-23-82, Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/106997; this version posted February 8, 2017. 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.
  • Molecular Structure of Promoter-Bound Yeast TFIID

    Molecular Structure of Promoter-Bound Yeast TFIID

    ARTICLE DOI: 10.1038/s41467-018-07096-y OPEN Molecular structure of promoter-bound yeast TFIID Olga Kolesnikova 1,2,3,4, Adam Ben-Shem1,2,3,4, Jie Luo5, Jeff Ranish 5, Patrick Schultz 1,2,3,4 & Gabor Papai 1,2,3,4 Transcription preinitiation complex assembly on the promoters of protein encoding genes is nucleated in vivo by TFIID composed of the TATA-box Binding Protein (TBP) and 13 TBP- associate factors (Tafs) providing regulatory and chromatin binding functions. Here we present the cryo-electron microscopy structure of promoter-bound yeast TFIID at a resolu- 1234567890():,; tion better than 5 Å, except for a flexible domain. We position the crystal structures of several subunits and, in combination with cross-linking studies, describe the quaternary organization of TFIID. The compact tri lobed architecture is stabilized by a topologically closed Taf5-Taf6 tetramer. We confirm the unique subunit stoichiometry prevailing in TFIID and uncover a hexameric arrangement of Tafs containing a histone fold domain in the Twin lobe. 1 Department of Integrated Structural Biology, Equipe labellisée Ligue Contre le Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67404, France. 2 Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France. 3 Institut National de la Santé et de la Recherche Médicale, U1258, 67404 Illkirch, France. 4 Université de Strasbourg, Illkirch 67404, France. 5 Institute for Systems Biology, Seattle, WA 98109, USA. These authors contributed equally: Olga Kolesnikova, Adam Ben-Shem. Correspondence and requests for materials should be addressed to P.S. (email: [email protected]) or to G.P.
  • Insights Into Regulation of Human RAD51 Nucleoprotein Filament Activity During

    Insights Into Regulation of Human RAD51 Nucleoprotein Filament Activity During

    Insights into Regulation of Human RAD51 Nucleoprotein Filament Activity During Homologous Recombination Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Ravindra Bandara Amunugama, B.S. Biophysics Graduate Program The Ohio State University 2011 Dissertation Committee: Richard Fishel PhD, Advisor Jeffrey Parvin MD PhD Charles Bell PhD Michael Poirier PhD Copyright by Ravindra Bandara Amunugama 2011 ABSTRACT Homologous recombination (HR) is a mechanistically conserved pathway that occurs during meiosis and following the formation of DNA double strand breaks (DSBs) induced by exogenous stresses such as ionization radiation. HR is also involved in restoring replication when replication forks have stalled or collapsed. Defective recombination machinery leads to chromosomal instability and predisposition to tumorigenesis. However, unregulated HR repair system also leads to similar outcomes. Fortunately, eukaryotes have evolved elegant HR repair machinery with multiple mediators and regulatory inputs that largely ensures an appropriate outcome. A fundamental step in HR is the homology search and strand exchange catalyzed by the RAD51 recombinase. This process requires the formation of a nucleoprotein filament (NPF) on single-strand DNA (ssDNA). In Chapter 2 of this dissertation I describe work on identification of two residues of human RAD51 (HsRAD51) subunit interface, F129 in the Walker A box and H294 of the L2 ssDNA binding region that are essential residues for salt-induced recombinase activity. Mutation of F129 or H294 leads to loss or reduced DNA induced ATPase activity and formation of a non-functional NPF that eliminates recombinase activity. DNA binding studies indicate that these residues may be essential for sensing the ATP nucleotide for a functional NPF formation.
  • Supplementary Table S1. Correlation Between the Mutant P53-Interacting Partners and PTTG3P, PTTG1 and PTTG2, Based on Data from Starbase V3.0 Database

    Supplementary Table S1. Correlation Between the Mutant P53-Interacting Partners and PTTG3P, PTTG1 and PTTG2, Based on Data from Starbase V3.0 Database

    Supplementary Table S1. Correlation between the mutant p53-interacting partners and PTTG3P, PTTG1 and PTTG2, based on data from StarBase v3.0 database. PTTG3P PTTG1 PTTG2 Gene ID Coefficient-R p-value Coefficient-R p-value Coefficient-R p-value NF-YA ENSG00000001167 −0.077 8.59e-2 −0.210 2.09e-6 −0.122 6.23e-3 NF-YB ENSG00000120837 0.176 7.12e-5 0.227 2.82e-7 0.094 3.59e-2 NF-YC ENSG00000066136 0.124 5.45e-3 0.124 5.40e-3 0.051 2.51e-1 Sp1 ENSG00000185591 −0.014 7.50e-1 −0.201 5.82e-6 −0.072 1.07e-1 Ets-1 ENSG00000134954 −0.096 3.14e-2 −0.257 4.83e-9 0.034 4.46e-1 VDR ENSG00000111424 −0.091 4.10e-2 −0.216 1.03e-6 0.014 7.48e-1 SREBP-2 ENSG00000198911 −0.064 1.53e-1 −0.147 9.27e-4 −0.073 1.01e-1 TopBP1 ENSG00000163781 0.067 1.36e-1 0.051 2.57e-1 −0.020 6.57e-1 Pin1 ENSG00000127445 0.250 1.40e-8 0.571 9.56e-45 0.187 2.52e-5 MRE11 ENSG00000020922 0.063 1.56e-1 −0.007 8.81e-1 −0.024 5.93e-1 PML ENSG00000140464 0.072 1.05e-1 0.217 9.36e-7 0.166 1.85e-4 p63 ENSG00000073282 −0.120 7.04e-3 −0.283 1.08e-10 −0.198 7.71e-6 p73 ENSG00000078900 0.104 2.03e-2 0.258 4.67e-9 0.097 3.02e-2 Supplementary Table S2.
  • Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association Between BMI and Adult-Onset Non- Atopic

    Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association Between BMI and Adult-Onset Non- Atopic

    Supplementary Material DNA Methylation in Inflammatory Pathways Modifies the Association between BMI and Adult-Onset Non- Atopic Asthma Ayoung Jeong 1,2, Medea Imboden 1,2, Akram Ghantous 3, Alexei Novoloaca 3, Anne-Elie Carsin 4,5,6, Manolis Kogevinas 4,5,6, Christian Schindler 1,2, Gianfranco Lovison 7, Zdenko Herceg 3, Cyrille Cuenin 3, Roel Vermeulen 8, Deborah Jarvis 9, André F. S. Amaral 9, Florian Kronenberg 10, Paolo Vineis 11,12 and Nicole Probst-Hensch 1,2,* 1 Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland; [email protected] (A.J.); [email protected] (M.I.); [email protected] (C.S.) 2 Department of Public Health, University of Basel, 4001 Basel, Switzerland 3 International Agency for Research on Cancer, 69372 Lyon, France; [email protected] (A.G.); [email protected] (A.N.); [email protected] (Z.H.); [email protected] (C.C.) 4 ISGlobal, Barcelona Institute for Global Health, 08003 Barcelona, Spain; [email protected] (A.-E.C.); [email protected] (M.K.) 5 Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain 6 CIBER Epidemiología y Salud Pública (CIBERESP), 08005 Barcelona, Spain 7 Department of Economics, Business and Statistics, University of Palermo, 90128 Palermo, Italy; [email protected] 8 Environmental Epidemiology Division, Utrecht University, Institute for Risk Assessment Sciences, 3584CM Utrecht, Netherlands; [email protected] 9 Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College, SW3 6LR London, UK; [email protected] (D.J.); [email protected] (A.F.S.A.) 10 Division of Genetic Epidemiology, Medical University of Innsbruck, 6020 Innsbruck, Austria; [email protected] 11 MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, W2 1PG London, UK; [email protected] 12 Italian Institute for Genomic Medicine (IIGM), 10126 Turin, Italy * Correspondence: [email protected]; Tel.: +41-61-284-8378 Int.
  • Genome-Wide DNA Methylation Analysis Reveals Molecular Subtypes of Pancreatic Cancer

    Genome-Wide DNA Methylation Analysis Reveals Molecular Subtypes of Pancreatic Cancer

    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 17), pp: 28990-29012 Research Paper Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer Nitish Kumar Mishra1 and Chittibabu Guda1,2,3,4 1Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA 2Bioinformatics and Systems Biology Core, University of Nebraska Medical Center, Omaha, NE, 68198, USA 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA 4Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA Correspondence to: Chittibabu Guda, email: [email protected] Keywords: TCGA, pancreatic cancer, differential methylation, integrative analysis, molecular subtypes Received: October 20, 2016 Accepted: February 12, 2017 Published: March 07, 2017 Copyright: Mishra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients.
  • ARID2 Deficiency Promotes Tumor Progression and Is Associated with Higher

    ARID2 Deficiency Promotes Tumor Progression and Is Associated with Higher

    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.10.898726; this version posted January 10, 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. ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer. Thaidy Moreno1, Laura González-Silva1, Beatriz Monterde1, Isabel Betancor-Fernández2, Carlos Revilla1, Antonio Agraz-Doblas1, Javier Freire3, Pablo Isidro4, Laura Quevedo1, Santiago Montes-Moreno3, Laura Cereceda3, Aurora Astudillo4, Berta Casar1,6, Piero Crespo1,6, Cristina Morales Torres5, Paola Scaffidi5,7, Javier Gomez-Roman3, Eduardo Salido2, and Ignacio Varela1* 1) Instituto de Biomedicina y Biotecnología de Cantabria. Universidad de Cantabria-CSIC. Santander, Spain. 2) Departamento de Patología, Centro de Investigación Biomédica en Red de Enfermedades Raras by impairing DNA repair. Importantly, our results indicate that ARID2-deficiency could be(CIBERER). Tenerife, Spain. 3) Servicio de Anatomía Patológica y Biobanco Valdecilla. HUMV/IDIVAL. Santander, Spain. 4) Biobanco del Principado de Asturias (BBPA). Hospital Universitario Central de Asturias. Oviedo, Spain. 5) Cancer Epigenetics Laboratory, The Francis Crick Institute. London, UK. 6) Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) 7) UCL Cancer Institute, London, UK. * To whom correspondence should be addressed: Ignacio Varela Instituto de Biomedicina y Biotecnología de Cantabria Universidad de Cantabria Albert Einstein 22, 39011 Santander Spain. Ph. +34 942203931 Email. [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.01.10.898726; this version posted January 10, 2020.
  • Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

    Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

    biomolecules Article Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Aayushi Srivastava 1,2,3,4 , Abhishek Kumar 1,5,6 , Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; [email protected] (A.S.); [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120 Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Received: 29 August 2019; Accepted: 10 October 2019; Published: 13 October 2019 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family.
  • TAF10 Complex Provides Evidence for Nuclear Holo&Ndash;TFIID Assembly from Preform

    TAF10 Complex Provides Evidence for Nuclear Holo&Ndash;TFIID Assembly from Preform

    ARTICLE Received 13 Aug 2014 | Accepted 2 Dec 2014 | Published 14 Jan 2015 DOI: 10.1038/ncomms7011 OPEN Cytoplasmic TAF2–TAF8–TAF10 complex provides evidence for nuclear holo–TFIID assembly from preformed submodules Simon Trowitzsch1,2, Cristina Viola1,2, Elisabeth Scheer3, Sascha Conic3, Virginie Chavant4, Marjorie Fournier3, Gabor Papai5, Ima-Obong Ebong6, Christiane Schaffitzel1,2, Juan Zou7, Matthias Haffke1,2, Juri Rappsilber7,8, Carol V. Robinson6, Patrick Schultz5, Laszlo Tora3 & Imre Berger1,2,9 General transcription factor TFIID is a cornerstone of RNA polymerase II transcription initiation in eukaryotic cells. How human TFIID—a megadalton-sized multiprotein complex composed of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs)— assembles into a functional transcription factor is poorly understood. Here we describe a heterotrimeric TFIID subcomplex consisting of the TAF2, TAF8 and TAF10 proteins, which assembles in the cytoplasm. Using native mass spectrometry, we define the interactions between the TAFs and uncover a central role for TAF8 in nucleating the complex. X-ray crystallography reveals a non-canonical arrangement of the TAF8–TAF10 histone fold domains. TAF2 binds to multiple motifs within the TAF8 C-terminal region, and these interactions dictate TAF2 incorporation into a core–TFIID complex that exists in the nucleus. Our results provide evidence for a stepwise assembly pathway of nuclear holo–TFIID, regulated by nuclear import of preformed cytoplasmic submodules. 1 European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, 38042 Grenoble, France. 2 Unit for Virus Host-Cell Interactions, University Grenoble Alpes-EMBL-CNRS, 6 rue Jules Horowitz, 38042 Grenoble, France. 3 Cellular Signaling and Nuclear Dynamics Program, Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, UMR 7104, INSERM U964, 1 rue Laurent Fries, 67404 Illkirch, France.
  • Natural Genetic Variation Caused by Small Insertions and Deletions in the Human Genome

    Natural Genetic Variation Caused by Small Insertions and Deletions in the Human Genome

    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research Natural genetic variation caused by small insertions and deletions in the human genome Ryan E. Mills,1,8 W. Stephen Pittard,2 Julienne M. Mullaney,3,4 Umar Farooq,3 Todd H. Creasy,3 Anup A. Mahurkar,3 David M. Kemeza,3 Daniel S. Strassler,3 Chris P. Ponting,5 Caleb Webber,5 and Scott E. Devine1,3,4,6,7,9 1Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA; 2Bimcore, Emory University, Atlanta, Georgia 30322, USA; 3Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA; 4Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA; 5MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom; 6Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA; 7Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA Human genetic variation is expected to play a central role in personalized medicine. Yet only a fraction of the natural genetic variation that is harbored by humans has been discovered to date. Here we report almost 2 million small insertions and deletions (INDELs) that range from 1 bp to 10,000 bp in length in the genomes of 79 diverse humans. These variants include 819,363 small INDELs that map to human genes. Small INDELs frequently were found in the coding exons of these genes, and several lines of evidence indicate that such variation is a major determinant of human biological diversity.