The Role of Insulators and Transcription Factors in Genome Organization and Function in Drosophila Open Access

Yang, Jingping (2012)

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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

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