Epigenetic Regulation and Sex Determination in the Germ Line of Caenorhabditis elegans Público
Li, Tengguo (2011)
Published
Abstract
Epigenetic Regulation and Sex Determination in the Germ Line
of
Caenorhabditis elegans
By Tengguo Li
Germ cells are the only cell type that contributes their genetic
and epigenetic components
to the next generation. They are developmentally totipotent and are
protected from
undergoing somatic differentiation throughout the germ line cycle.
Germ cells at different
developmental stages are marked with different epigenetic
signatures that are correlated
with their properties. The methylation of histone H3 on Lysine 4
(H3K4me) has been
identified as both a mark of active transcription and a potential
component of "epigenetic
memory". We have demonstrated that the global maintenance of H3K4
methylation in C.
elegans germ cells requires the homologues of components of
a conserved H3K4
methyltransferase complex, the Set1/MLL complex. Interestingly,
Set1/MLL component-
dependent methyltransferase activity can methylate H3K4
independently of ongoing
transcription in early embryonic germ line and somatic blastomeres,
and also in adult
germ line stem cells. A separate H3K4 methylation mechanism that
operates
independently of Set1/MLL component activities appears to correlate
more directly with
transcription. We propose that H3K4 methylation is maintained
throughout the germ cell
cycle by alternating transcription dependent and independent
mechanisms.
WDR-5.1, one of the conserved Set1/MLL components, plays an
essential role in
the regulation of methyltransferase activity. Mutation of
wdr-5.1 affects both germ line
stem cell population size and normal germ cell development.
Notably, double mutation of
wdr-5.1 and its paralog wdr-5.2 exhibits severe germ
line sex determination defects.
TRA-1, a transcriptional repressor required for oogenesis, does not
localize to chromatin
in the absence of both wdr-5.1 and wdr-5.2. This
disruption of the interaction between
TRA-1 and chromatin results in the ectopic expression of
fog-3, which subsequently
causes the masculinization of the germ line (Mog). We also
identified set-9 and set-26 as
sex determination regulators that may function redundantly with
WDR-5.1 and WDR-5.2.
Together, these data suggest that the components of Set1/MLL
complex play a critical
role in mediating epigenetic and genetic networks that are
essential for proper germ line
stem cell maintenance and germ cell development.
Table of Contents
TABLE OF CONTENTS
Chapter 1: Introduction 1
Epigenetics: an overview 2
DNA methylation and
epigenetic regulation 2
Chromatin as an organizer and carrier for epigenetic information
3
Function of histone modifications 6
Regulation and implications of H3K4 methylation 11
Implications for diseases 16
Overview of Germ cells 18
C. elegans as
a model system for germ cell biology 18
Gene repression is a common feature during germ cell specification
21
Two modes of germ cell specification 24
Epigenetic regulation of germ cells specification and development
25
Scope of dissertation 30
Chapter 2: A Role for Set1/MLL Related Components in
Regulation of the
Caenorhabditis elegans Germ Line 43
Introduction 46
Results 52
Discussion 71
Materials and Methods 79
Chapter 3: WDR-5 Is Involved in Regulation of Sex
Determination of
Caenorhabditis elegans 130
Introduction 131
Results 136
Discussion 148
Materials and Methods 154
Chapter 4: Discussion and Future Directions 182
References 195
About this Dissertation
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