Epigenetic Regulation of the Major Histocompatibility Complex Class II Genes Público

Abstract

Abstract
Epigenetic Regulation of the Major Histocompatibility Complex Class II Genes
The major histocompatibility complex class II genes (MHC-II) are a fundamental part of our adaptive
immune system. Without proper expression of these genes, our bodies fail to mount an
effective response against bacterial and viral infections, or may also lead to cancer and
autoimmune diseases. The class-II transactivator (CIITA) is regarded the master regulator
of MHC-II genes. CIITA can recruit various transcriptional coactivators to the promoter of
MHC-II genes to activate transcription, such as CBP/p300 and PCAF. These transcription
factors can modify histones positioned at cis-regulatory sites to alter the transcription level
of genes. At an MHC-II gene, HLA-DRA, various histone acetylation and methylation
modifications accumulated with the activation of transcription in both B cells and epithelial
cells treated with interferon-γ, but not in mutant B cells that were lacking the expression of
essential transcription factors. Using a dual-crosslinking chromatin immunoprecipitation
approach, multiple subunits of the histone methyltransferase complex MLL and histone
acetyltransferase complexes STAGA and ATAC were determined to bind at various regions
across the gene and regulatory regions. In an unbiased approach to discover novel CIITA
interacting proteins, a biotin-ligase-recognition-peptide fusion CIITA expression construct
was cloned and expressed in B cells. By tandem mass spectrometry, the interacting proteins
were determined. Recently, a genome-wide association study determined that a single
nucleotide polymorphism within the first intron of HLA-DRA was highly correlated with
late-onset Parkinson's disease (PD). It was hypothesized that a novel cis-regulatory element
may be within its close proximity. PD and control whole blood samples were collected, and
MHC-II expression levels were assessed in B cells and monocytes. Through these and
further studies, a greater understanding is gained of the factors involved in MHC-II gene
expression and how the expression of these genes influence various humans diseases.

Table of Contents

Table of Contents
Abstract
Acknowledgements
List of Figures and Tables
Chapter 1. Introduction----------------------------------------------------------------------------1
Introduction - Part 1 - -----------------------------------------------------------------------------1
MHC-II Complex Function And Its Role In The Immune System --------------------------------1
Antigen Presentation By Major Histocompatibility Complexes-----------------------------------3
Essential Regulatory Elements of MHC-II Transcription------------------------------------------7
Histone Modifications and Transcriptional Regulation-------------------------------------------12
Histone Modifying Complexes and Their Role in Transcriptional Regulation-------------------16
Introduction - Part 2 - Regulation of Major Histocompatibility Complex Class II Genes------23
Summary -----------------------------------------------------------------------------------------24
Introduction---------------------------------------------------------------------------------------24
MHC-II promoter proximal elements and factors-----------------------------------------------25
MHC-II epigenetic regulation through histones-------------------------------------------------28
Long-range chromosomal regulation of MHC-II-------------------------------------------------30
Conclusion----------------------------------------------------------------------------------------35
References----------------------------------------------------------------------------------------35
Figure Legends-----------------------------------------------------------------------------------42
Chapter 2. Multiple Histone Methyl and Acetyltransferase Complex Components Bind the
HLA-DRA Gene -----------------------------------------------------------------------------------46
Abstract-------------------------------------------------------------------------------------------47
Introduction--------------------------------------------------------------------------------------48
Materials and Methods---------------------------------------------------------------------------52
Results--------------------------------------------------------------------------------------------56
Discussion-----------------------------------------------------------------------------------------67
References----------------------------------------------------------------------------------------73
Figure Legends-----------------------------------------------------------------------------------82
Tables---------------------------------------------------------------------------------------------89
Figures--------------------------------------------------------------------------------------------90
Chapter 3. Purification of the CIITA Interacting Protein Complex ---------------------------102
Introduction-------------------------------------------------------------------------------------103
Materials and Methods--------------------------------------------------------------------------106
Results-------------------------------------------------------------------------------------------112
Discussion---------------------------------------------------------------------------------------116
Figure Legends----------------------------------------------------------------------------------118
Figures-------------------------------------------------------------------------------------------121
Tables--------------------------------------------------------------------------------------------126
Chapter 4. The role of a single nucleotide polymorphism within the MHC-II gene,
HLA-DRA, in Parkinson's disease---------------------------------------------------------------129
Introduction-------------------------------------------------------------------------------------130
Materials and Methods--------------------------------------------------------------------------132
Results-------------------------------------------------------------------------------------------136
Discussion---------------------------------------------------------------------------------------140
Figure Legends----------------------------------------------------------------------------------141
Figures-------------------------------------------------------------------------------------------145
Tables--------------------------------------------------------------------------------------------151
Chapter 5. Conclusions and Discussions-------------------------------------------------------156
References Cited in Chapter 1 - Part 1 - & Chapters 3 to 5-----------------------------------166

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Biochemistry, Cell & Developmental Biology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics Health Sciences, General Health Sciences, Immunology
Palabra Clave	CIITA Parkinson's Disease Epigenetic MHC-II histone
Committee Chair / Thesis Advisor	Boss, Jeremy, Emory University
Committee Members	Lucchesi, John, Emory University Kelly, William G, Emory University Speck, Sam, Emory University Cheng, Xiaodong, Emory University

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