The CIITA regulation during B cell differentiation to plasma cell Open Access

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

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biomedical Engineering
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics
Keyword	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

Last modified

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	The CIITA regulation during B cell differentiation to plasma cell ()	2018-08-28 13:24:06 -0400	Press to Select an action Download

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions