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Download The BIOCHEMICAL CHARACTERIZATION AND REGULATION OF TRANSCRIPTION OF POLYCOMB GROUP RING FINGER 5 by Christopher Larson Cochrane B.Sc., The University of British Columbia, 2004 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2013 © Christopher Larson Cochrane, 2013 Abstract The Polycomb Group (PcG) is a highly conserved group of genes which serve to repress transcription via specific modifications of histones in chromatin. The PcG has well-established roles in development and is involved, by mutation or dysregulation, in many human diseases including cancer. This study identifies the gene PCGF5, which is a paralogue of the oncogene Bmi1, as a transcriptional target of Notch signalling in T cell acute lymphoblastic leukemia (T-ALL). Evidence suggests that this regulation is direct and that the Notch transactivation complex binds DNA at several regions near the PCGF5 gene. PCGF5 is found to be expressed at a higher level in T-ALL than other hematopoietic malignancies. PCGF5 is found to associate with the PcG proteins RING1A and RING1B and its overexpression results in increased ubiquitylation of histone H2A, suggesting it shares functional similarity to Bmi1. Despite their similarities, Bmi1 and PCGF5 have a different spectrum of binding partners and are targeted to different locations in the genome. Overexpression of PCGF5 does not significantly alter hematopoietic development in vivo; however, enforced expression of PCGF5 in bone marrow progenitors results in the generation of fewer colonies in a myeloid colony forming assay. This study suggests that PCGF5 may have as yet unappreciated roles in PcG biology and merits further study into its effects on development and hematopoietic neoplasia. ii Table of Contents Abstract ......................................................................................................................................................... ii List of Tables .............................................................................................................................................. viii List of Figures ............................................................................................................................................... ix Abbreviations ..............................................................................................................................................xiii Acknowledgments ........................................................................................................................................ xx Dedication ................................................................................................................................................... xxi Chapter 1 Introduction ................................................................................................................................. 1 1.1 Rationale ............................................................................................................................................. 1 1.2 The Polycomb Group of genes ............................................................................................................ 2 1.2.1 Genetics ....................................................................................................................................... 2 1.2.2 Polycomb genes in mammals....................................................................................................... 3 1.2.3 Defining the PcG complex ............................................................................................................ 5 1.2.4 Histone modification .................................................................................................................... 9 1.2.5 Targeting and recruitment ......................................................................................................... 11 1.3 Epigenetics and the histone code ..................................................................................................... 12 1.3.1 The epigenetic code ................................................................................................................... 12 1.3.2 Histone modifications ................................................................................................................ 13 1.4 The Notch signalling pathway ........................................................................................................... 17 1.4.1 Notch genetics ........................................................................................................................... 17 iii 1.4.2 The Notch transactivation complex ........................................................................................... 18 1.4.3 Mechanism of signal transduction ............................................................................................. 18 1.4.4 Notch and T cell Acute Lymphoblastic Leukemia ...................................................................... 19 1.4.5 Hypotheses................................................................................................................................. 20 Chapter 2 Materials and methods ............................................................................................................. 23 Chapter 3 Notch signalling regulates expression of PCGF5 in T cell Acute Lymphoblastic Leukemia cells33 3.1 Introduction ...................................................................................................................................... 33 3.2 Results ............................................................................................................................................... 35 3.2.1 Identification of PCGF5 as a target of Notch ............................................................................. 35 3.2.2 Notch activation of PCGF5 expression does not require do novo protein translation .............. 42 3.2.3 Notch binds upstream of the PCGF5 locus ................................................................................ 42 3.2.4 Notch1 and CSL binding of PCGF5 locus is significantly higher than expected by chance ........ 50 3.2.5 PCGF5 expression in T-ALL cases ............................................................................................... 52 3.2.6 Tissue distribution ...................................................................................................................... 55 3.2.7 Splice variants and genomic organization ................................................................................. 58 3.3 Discussion .......................................................................................................................................... 59 3.3.1 Notch transcriptional regulation of PCGF5 ................................................................................ 59 3.3.2 Notch and CSL binding of the PCGF5 locus ................................................................................ 67 3.3.3 Notch expression in cancer ........................................................................................................ 69 3.3.4 PCGF5 and Notch linked in normal development ...................................................................... 70 iv Chapter 4 PCGF5 overexpression does not alter steady state hematopoiesis but results in reduced myeloid colony output by bone marrow progenitors ................................................................................ 72 4.1 Introduction ...................................................................................................................................... 72 4.1.1 The role of Notch in lymphopoiesis ........................................................................................... 72 4.1.2 Notch and T-cell Acute Lymphoblastic Leukemia ...................................................................... 73 4.1.3 The role of Bmi1 and the Polycomb Group in lymphopoiesis ................................................... 74 4.1.4 Experimental approaches .......................................................................................................... 76 4.1.5 Hypotheses................................................................................................................................. 77 4.2 Results ............................................................................................................................................... 77 4.2.1 Overexpression of neither PCGF5 nor Bmi1 causes significant alterations to hematopoiesis in bone marrow transplant recipients .................................................................................................... 77 4.2.2 PCGF5 does not alter lymphoid progenitor performance in OP9 coculture assay .................... 89 4.2.3 PCGF5 causes reduced myeloid CFC output in bone marrow progenitors ................................ 97 4.3 Discussion ........................................................................................................................................ 101 4.3.1 Comment on Experimental Design .......................................................................................... 101 4.3.2 PCGF5 overexpression in bone marrow does not alter engraftment or multilineage reconstitution in transplant recipients ............................................................................................
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