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'Identification of Cell Type Enriched Cofactors of NF-Κb Dependent Transcription'

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'Identification of Cell Type Enriched Cofactors of NF-Κb Dependent Transcription' Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2006 Identification of cell type enriched cofactors of NF-฀B dependent transcription Owen, Heather R Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-163590 Dissertation Published Version Originally published at: Owen, Heather R. Identification of cell type enriched cofactors of NF-฀B dependent transcription. 2006, University of Zurich, Faculty of Science. Identification of Cell Type Enriched Cofactors of NF-κB Dependent Transcription Dissertation Zur Erlangung der naturwissenshaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Heather R. Owen Aus Grossbritannien Promotionskomitee Prof. Dr. Dr. Michael O. Hottiger Prof. Dr. Walter Schaffner Prof. Dr. Michael Hengartner Zürich, 2006 1 Summary A multi-cellular organism has many different types of cell and each is characterised by a particular morphology and metabolism to perform a specialised function. Variation occurs between the cell types despite the fact that every cell in an organsism has the same genetic material. The physiology of each individual cell type is due to differences in the expression of proteins, the molecular workers of the cellular factory. Proteins are coded for by genes and one of the major levels of regulation of gene expression is through transcription. Transcription of genes is the molecular process where RNA polymerase II (RNAPII) transfers the DNA code into an RNA code. This process is regulated at multiple steps by transcription factors and their cofactors. The chromatin structure also has a role in transcription regulation since the DNA must be accessible to transcriptional regulators for RNAPII activity. Nuclear Factor kappa B (NF-κB) is a family of inducible transcription factors responsible for transcription of a wide variety of genes upon cellular stimulation with a huge array of factors. RelA (also called p65) is a major member of this family and is expressed in all cell types. The transcription of NF-κB regulated genes may be regulated according to the cell type due to a cell type specific chromatin status and cell type enriched cofactors. The aim of this thesis was to identify novel cell type enriched cofactors of RelA(p65) dependent transcription. A proteomics approach was used to isolate and identify proteins that interact with the transcription activation domain (TAD) of RelA(p65). Known and novel cofactors of RelA(p65)-TAD were identified. Among others, a novel RelA(p65)-TAD interaction partner, called MYB binding protein 1a (MYBBP1a), was found as a cell type enriched factor. MYBBP1a was detected to repress NF-κB regulated transcription in vivo and in vitro and to compete with a co-activator for interaction with the TAD of RelA(p65). The work presented in this thesis shows the identification of cell type enriched cofactors of NF- κB and indicates that the cofactor occupancy of RelA(p65) could be important in the regulation of cell type specific gene expression. 2 Zusammenfassung Ein vielzelliger Organismus besteht aus vielen verschiedenen Zelltypen, die aufgrund verschiedener Morphologien und Metabolismen spezialisierte Funktionen übernehmen können. Obwohl jede Zelle in einem Organismus das gleiche genetische Material aufweist, treten Unterschiede zwischen den verschiedenen Zelltypen auf. Die Physiologie jedes Zelltyps beruht auf der unterschiedlichen Expression von Proteinen, den molekularen Regulatoren der zellulären Maschinerie. Proteine wiederum werden von Genen kodiert; diese werden zum grossen Teil auf Ebene der Transkription reguliert. Gentranskription ist der molekulare Prozess, bei welchem die RNS Polymerase II (RNAPII) die Information der DNS in RNS überschreibt. Dieser Prozess wird auf verschiedenen Ebenen durch Transkriptionsfaktoren und ihre Kofaktoren reguliert. Auch die Chromatinstruktur spielt eine Rolle, da die DNS für die Regulatoren der RNAPII-Aktivität zugänglich sein muss. Nukleärer Faktor kappa B (NF-κB) ist eine Familie von induzierbaren Transkriptionsfaktoren. Nach zellulärer Stimulation durch eine Vielzahl von Faktoren sind sie verantwortlich für die Transkription einer breiten Anzahl von Genen. Das wichtigste Mitglied dieser Familie ist RelA (auch p65 genannt), welches in allen Zelltypen exprimiert wird. Für die Transkription von Genen, welche von NF-κB reguliert werden, sind auch der zelltyp-spezifische Chromatinstatus und Kofaktoren, welche in diesem Zelltyp angereichert sind, wichtig. Das Ziel dieser Doktorarbeit war es, neue zelltyp-spezifische Kofaktoren der RelA(p65)- abhängigen Transkription zu identifizieren. Dafür wurde eine spezielle Proteomics-Methode angewendet um Proteine zu isolieren und identifizieren, welche mit der Transkriptions-Aktivierungs- Domäne (TAD) von p65 interagieren. So wurden bekannte und auch neue Kofaktoren von p65-TAD identifiziert. Einer dieser neuen Interaktionspartner, MYB Bindendes Protein 1a (MYBBP1a), stellte sich als zelltyp-spezifisch angereicherter Faktor heraus. MYBBP1a reprimierte NF-κB regulierte Transkription in vivo und in vitro und konkurrierte mit einem bekannten Ko-Aktivator um die Bindung an die TAD von p65. Die in dieser Doktorarbeit präsentierten Ergebnisse bestätigen die Identifikation von zelltyp-spezifischen Kofaktoren für NF-κB und weisen darauf hin, dass die Komplexbildung von RelA(p65) mit Kofaktoren eine wichtige Rolle in der Regulation der Genexpression spielt. 3 Table of Contents SUMMARY................................................................................................................................................... 2 ZUSAMMENFASSUNG.............................................................................................................................. 3 TABLE OF CONTENTS............................................................................................................................. 4 ABBREVIATIONS ...................................................................................................................................... 6 INTRODUCTION........................................................................................................................................ 8 1 THE MECHANISM OF RNA POLYMERASE II TRANSCRIPTION .......................................... 8 1.1 THE GENERAL TRANSCRIPTION INITIATION MACHINERY ................................................................ 9 1.1.1 RNA Polymerase II ................................................................................................................. 9 1.1.2 The transcription cycle ........................................................................................................... 9 1.2 THE SUBSTRATE FOR TRANSCRIPTION ........................................................................................... 12 1.2.1 The core promoter ................................................................................................................ 12 1.2.2 Enhancers, proximal promoters, silencers and Insulators ................................................... 14 1.2.3 Nucleosome structure ........................................................................................................... 15 1.2.4 Histone structure and the histone code................................................................................. 16 1.2.5 Higher order chromatin structure ........................................................................................ 18 1.2.6 Heterochromatin and Euchromatin...................................................................................... 19 1.2.7 Transcription factories ......................................................................................................... 20 1.2.8 Nuclear Structure ................................................................................................................. 20 1.3 REGULATION OF TRANSCRIPTION .................................................................................................. 22 1.3.1 Transcription Factors (TFs)................................................................................................. 22 1.3.2 Transcription cofactors ........................................................................................................ 24 2 NF-κB DEPENDENT TRANSCRIPTION ....................................................................................... 26 2.1 THE MAMMALIAN NF-κB FAMILY MEMBERS ................................................................................ 26 2.2 SIGNAL TRANSDUCTION PATHWAYS .............................................................................................. 27 2.3 SIGNAL SPECIFICITY OF THE NF-κB RESPONSE .............................................................................. 30 2.3.1 Degradation of specific IκB proteins.................................................................................... 31 2.3.2 Activation of transcription by specific NF-κB dimers .......................................................... 31 2.3.3 Cooperation with other TFs and cofactors........................................................................... 32 2.3.4 Post translational modifications (PTMs).............................................................................. 32 2.4 κB BINDING IN VITRO AND IN VIVO ................................................................................................ 32 2.5
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