Abstract
Epigenetic changes can alter the genome function without
altering their base composition. These differences can be inherited
and can provide an important source of variation within populations
that can be acted upon by natural selection. Epigenetic changes in
gene expression can take place via covalent modifications of
histone or DNA as well as the three-dimensional organization of
chromatin in the nucleus. Insulators mediate chromatin interactions
in cis or trans between different regions of the
genome and may be important factors regulating the 3D organization
of the genome. BEAF-32 is an insulator protein highly
conserved in Drosophila but not found in other species. Here
I describe an analysis of the epigenetic function of BEAF-32 in
Drosophila. I identify the BEAF-32 insulator as a cis
regulatory element separating genes arranged in a head-to-head
orientation. I then compare the genome-wide binding landscapes of
the BEAF-32 in four different Drosophila species and
highlight the evolutionarily conserved presence of this protein
between close adjacent genes. During the formation of new
Drosophila species, binding of BEAF-32 in the genome is
altered along with changes in genome organization caused by DNA
re-arrangements. The alterations of BEAF-32 distribution correlate
with new gene expression profiles, which in turn translate into
specific and distinct phenotypes. Epigenetic information encoded in
the 3D organization of the genome mediated by insulators needs to
be faithfully transmitted through mitosis and meiosis in order to
effect evolutionary change. To address this issue, I have also
studied the function of the Myc transcription factor. I found that
a subset of Myc sites remain on mitotic chromatin and overlap with
aligned insulator proteins binding sites. These sites are enriched
at the boundaries of topological chromosome domains, suggesting
they may be important for maintaining chromosome structure
throughout the cell cycle. Together, these results suggest a
mechanism for the establishment of differences in transcription
patterns during evolution and may help to decipher the role of
epigenetic changes in evolution.
Table of Contents
Chapter 1: Introduction 1
Chapter 2: The BEAF-32 insulator coordinates genome
organization and function during the evolution of Drosophila
species
Abstract 17
Introduction 18
Results 21
BEAF-32 specifically associates with close head-to-head gene pairs
21
BEAF-32-associated close head-to-head gene pairs are not
co-expressed 22
BEAF-32 separates close head-to-head genes with different patterns
of transcription regulation 23
Conservation and diversity of BEAF-32 insulators across Drosophila
species 25
Changes of BEAF-32 insulator localization correlate with
alterations in genome organization during Drosophila evolution
27
Alterations in BEAF-32 insulator localization correlate with
changes of genome function during Drosophila evolution 29
Discussion 32
Methods 35
Acknowledgments 43
Chapter 3: A specific subset of Drosophila Myc sites remains
associated with mitotic chromosomes co-localized with insulator
proteins
Abstract 81
Introduction 82
Results 85
Myc is present at the promoters of paused genes 85
The role of Myc at non-promoter regions 86
Myc associates with Orc2 genome-wide in D. melanogaster 87
A distinct subset of Myc sites remains bound to chromosomes during
mitosis 88
The two classes of Myc sites may have different roles in gene
expression 99
Mitotic Myc sites are present at a subset of promoters but not
enhancers 90
Myc sites of unknown function associate with insulators 91
Myc mitotic sites associate with mitotic insulator sites 92
Mitotic Myc sites are enriched at the borders of topological
chromosomal domains 93
Discussion 95
Methods 98
Acknowledgements 102
Chapter 4: Discussion 115
Reference 121
About this Dissertation
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