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Dissertation Dissertation Submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the Degree of Doctor of Natural Sciences Presented by Michael Delacher (M.Sc.) Born in Ulm, Germany Oral Examination: April 7 th, 2016 Transcriptional Control of Regulatory T cells Referees Dr. Markus Feuerer Prof. Dr. Viktor Umansky This dissertation was performed and written during the period from July 2012 to December 2015 at the German Cancer Research Center (DKFZ) and the Weizmann Institute of Science (WIS) under the supervision of Prof. Dr. Viktor Umansky and joint direct supervision of both Dr. Markus Feuerer (DKFZ) and Dr. Jakub Abramson (WIS). The dissertation was submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto- Carola University of Heidelberg, Germany in January 2016. German Cancer Research Center (DKFZ) Tumor Immunology Program Research Group Immune Tolerance (D100) Im Neuenheimer Feld 280 69120 Heidelberg Germany Weizmann Institute of Science (WIS) Faculty of Biology Department of Immunology Laboratory of Dr. Jakub Abramson Hertzl 234 Street 76100 Rehovot Israel Declaration I herewith declare that I performed and wrote this dissertation independently under supervision and used no other sources and aids than those indicated. Furthermore, I declare that I have not submitted this thesis for a degree to any other academic or similar institution. No parts of this dissertation were published prior to the submission to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg. Parts of the experiments in this dissertation were performed in collaboration with other research groups as follows: • CG methylation analysis with the 454 pyrosequencing technology: Division of Epigenetics, DKFZ, Heidelberg Dr. Achim Breiling & Prof. Dr. Frank Lyko • Sample preparation and allocation of Dnmt1-hypomorphic mice: Laboratory of Molecular Stem Cell Biology, Münster University, Münster Melinda Czeh & Prof. Dr. Frank Rosenbauer • Proteomics on EL4 T cells with inverted ChIP technology: Genome Biology Unit, EMBL, Heidelberg Dr. Katrin Eichelbaum & Dr. Jeroen Krijgsveld • Generation of viral constructs for T cell transduction and luciferase measurements: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel Yonatan Herzig & Dr. Jakub Abramson • Preparation of H&E staining and pathological evaluation: Division of Cellular and Molecular Pathology, DKFZ, Heidelberg Dr. Guiseppina Federico & Prof. Dr. Hermann-Josef Gröne • Tagmentation-based whole genome sequencing of tissue-resident T cells: Department of Epigenomics and Cancer Risk Factors, DKFZ, Heidelberg Dr. Dieter Weichenhan & Prof. Dr. Christoph Plass • Bioinformatic computation of next-generation sequencing data: Division of Applied Bioinformatics, DKFZ, Heidelberg Charles Imbusch & Prof. Dr. Benedikt Brors ____________________________ _______________________________ (Place/Date) (Signature) Table of Contents 1 Summary ................................................................................................................................... 1 ! 2 Zusammenfassung .................................................................................................................... 3 ! 3 Acknowledgements ................................................................................................................... 5 ! 4 Background ............................................................................................................................... 7 ! 4.1 T cells originate from hematopoietic stem cells ............................................................................ 7 ! 4.2 Central tolerance is mediated by thymus-resident TEC ................................................................ 8 ! 4.3 Peripheral tolerance is mediated by regulatory T cells ................................................................. 9 ! 4.4 tTreg cells are born in the thymus, whereas pTreg cells are induced locally ............................. 10 ! 4.5 Treg cells suppress pro-inflammatory effector cells ................................................................... 12 ! 4.6 Treg cells express key lineage proteins related to their function ................................................ 14 ! 4.7 Treg cells are distributed throughout the body and take on tissue-specific protective functions 16 ! 4.8 Treg cell depletion as cancer therapy .......................................................................................... 18 ! 4.9 Treg cell adoptive transfer to combat autoimmune disease ........................................................ 22 ! 4.10 Scope of this thesis .................................................................................................................... 24 ! 5 Introduction ............................................................................................................................ 25 ! 5.1 Epigenetic control of the Foxp3 gene in Treg cells .................................................................... 25 ! Epigenetics is the study of DNA methylation and histone/nucleosome modifications ............................... 25 ! Methylation of cytosine residues in CpG islands can control gene expression .......................................... 26 ! Sodium bisulfite sequencing and other methods to investigate DNA methylation ..................................... 27 ! Zygotes become demethylated and require DNA-methyltransferase to regain epigenetic control ............. 28 ! Epigenetics and disease ............................................................................................................................... 29! Methylation analysis of the Foxp3 gene reveals the Treg-specific demethylated region (TSDR) ............. 30 ! Aim of this subproject ................................................................................................................................. 31! 5.2 Transcriptional and epigenetic control of tissue-specific Treg cells ........................................... 32 ! Global H3K4me3 and H3K27me3 study in Treg cells ............................................................................... 32 ! Global MeDIP-Seq of Treg cells reveals 300 Treg-specific demethylated regions .................................... 33 ! Aim of this subproject ................................................................................................................................. 34! 5.3 Transcription-factor based control of the Foxp3 gene ................................................................ 36 ! Gene conservation studies reveal highly conserved non-coding sequences (CNS) .................................... 36 ! Signaling Pathways involved in the regulation of Foxp3 gene expression ................................................. 37 ! The Foxp3 promoter can bind several TF to induce Foxp3 gene transcription ........................................... 38 ! The CNS1 region is important for peripheral, but not thymic, induction of Treg cells .............................. 40 ! The CNS2 stabilizes Foxp3 gene expression by selective CG demethylation ............................................ 41 ! CNS3 is a pioneer element required for efficient induction of Foxp3 transcription ................................... 42 ! Aim of this subproject ................................................................................................................................. 42! 5.4 Rbpj and its function for Treg cell homeostasis .......................................................................... 43 ! The Notch Signaling Pathway ..................................................................................................................... 43! Notch ligands induce Notch signaling to regulate many aspects of mammalian life .................................. 44 ! Notch signaling in hematopoietic stem cell development and cell fate decision ........................................ 45 ! Notch signaling controls thymic T-cell development ................................................................................. 46 ! The IL7R is induced by Notch/Rbpj and promotes T-cell expansion and survival .................................... 47 ! Peripheral T cells express Notch receptors upon activation ........................................................................ 48 ! Dll ligands can induce T H1 differentiation of peripheral T cells ................................................................. 48! Jagged ligands promote T H2 subset differentiation ..................................................................................... 49! Dll4 ligand drives T H17 subset differentiation ............................................................................................ 50! Aim of this subproject ................................................................................................................................. 51! 6 Materials and Methods .......................................................................................................... 53 ! 6.1 Epigenetic control of the Foxp3 gene in Treg cells .................................................................... 53 ! Mice ............................................................................................................................................................. 53! Cell isolation and cell sorting
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