The CIITA regulation during B cell differentiation to plasma cell Open Access
Yoon, Hyesuk (2010)
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.
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