The CIITA regulation during B cell differentiation to plasma cell Public

Abstract

The CIITA Regulation during B cell differentiation to plasma cell

By Hyesuk Yoon
CIITA, the transcriptional activator of MHC class II expression, is controlled by at least three
distinct promoters, pI, pIII, and pIV in a cell type and developmental specific manner. The
promoter III regulatory regions that control constitutive CIITA expression in B cells have been
characterized; however, other distal regulatory regions that may be required for CIITA regulation
have not been identified. By applying a number of approaches, HSS1 (hypersensitive site 1)
located 11kb upstream of pIII, was identified as a distal regulatory element involved in CIITA
activation B cells. PU.1, an ETS domain containing transcriptional factor, which is essential for
lymphocyte development, binds to HSS1 and directs long-range chromosomal interactions
between HSS1 and CIITA pIII in B cells. Additionally, several CTCF (CCCTC binding factor)
binding sequences on CIITA genes were found. These sites displayed an enhancer-blocking
insulator activity, suggesting the possibility that these CTCF sites may be also involved in
chromosomal interaction with HSS1 and pIII. CIITA is regulated by cell-type specific
transcription factors. ZBTB32/ROG(repressor of GATA3) was identified as a novel repressor of
class II transactivator (CIITA) and MHC-II gene expression during the early phase of plasma cell
differentiation. ZBTB32 knock out mice showed delayed repression of CIITA and BCL6 mRNA,
and lower levels of Blimp-1 mRNA expression compared to wild-type mice during B cell
differentiation. Knockdown of ZBTB32 in plasma cells increased CIITA expression, as well as
other B cell fate regulators, such as Pax5 and SpiB. In plasma cells, ZBTB32 and the Polycomb
repressor complex bound directly to the CIITA promoter prior to Blimp-1 binding. ZBTB32 and
Blimp-1 coimmunoprecipitated and co-localized within the nucleus. These results suggest that

ZBTB32 initiates CIITA silencing during B cell differentiation and may important role in plasma
cell formation. In summary, the data reported in this thesis introduce novel cis-regulatory
elements and transcriptional factors that are required for CIITA regulation during B cell
differentiation.

Table of Contents

TABLE OF CONTENTS

Abstract
List of Figures and Tables
I. Introduction - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1
Antigen processing and presentation - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1
Regulation of MHC class II gene expression - - - - - - - - - - - - - - - - - - - - - - - 6
CIITA related disease (Bare lymphocyte syndrome) - - - - - - - - - - - - - - - - - - 7
Transcriptional factors binding to MHC class II promoters - - - - - - - - - - - - - 8
CIITA structure, MHC class II expression - - - - - - - - - - - - - - - - - - - - - - - 10
CIITA gene locus - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 11
B cell differentiation and CIITA expression - - - - - - - - - - - - - - - - - - - - - - 17
B cell specific transcription factor - - - - - - - - - - - - - - - - - - - - - - - - - 20
Plasma cell specific transcription factor - - - - - - - - - - - - - - - - - - - - - - 22
CIITA regulation during B cell differentiation - - - - - - - - - - - - - - - - - 25
Chromatin structure during B cell differentiation in CIITA gene - - - - - 26
CIITA regulation by distal regulatory elements - - - - - - - - - - - - - - - - - 28
Summary - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 30
II. Materials and Methods - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 32
III. Studies - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 41
Chapter 1. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 42

PU.1 binds to a distal regulatory element that is necessary for B-cell specific
expression of the class II transactivator.

About this Dissertation

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School	Laney Graduate School
Department	Biomedical Engineering
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics
Mot-clé	CIITA B cell plasma cell
Committee Chair / Thesis Advisor	Boss, Jeremy, Emory University
Committee Members	Lucchesi, John, Emory University Speck, Sam, Emory University Moran Jr., Charles, Emory University Vertino, Paula M, Emory University

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