Regulatory mechanisms of heterochromatin dynamics during Caenorhabditis elegans meiosis Pubblico
Fedotov, Alexander Vyacheslavovich (2012)
Abstract
Major changes to higher-order chromatin architecture are tightly linked to all key meiotic processes that ensure proper juxtaposition of homologous chromosomes and their precise segregation during gametogenesis. Heterochromatic domains pose specific challenge for the maintenance of genome stability during homologous recombination due to their repetitive nature. Our understanding of the principles that govern organization of these domains during meiosis is limited. The overall goal of the work described in my dissertation is to determine the mechanisms that regulate dynamics of histone H3 lysine 9 methylation (H3K9me2), a hallmark of heterochromatin, in Caenorhabditis elegans meiosis.
Using a combination of three-dimensional high-resolution microscopy, data mining, and cytogenetic approaches, I revealed previously unrecognized heterochromatin-specific reorganization events at the onset of meiosis that depend upon assembly of meiotic scaffold of chromosomes. I demonstrated that an early association of central region components of synaptonemal complex with chromatin takes place prior to pairing and alignment of homologs, and is mediated by dynein motors. This step of chromosomal axis morphogenesis is required for the establishment of H3K9me2-enriched chromatin compartments, which are later sequestered by the maturing proteinaceous scaffold. I also uncovered the existence of sex-specific differences in the organization of heterochromatin in the context of meiotic scaffold.
My studies therefore provide the first example of the histone modification defining an interface of juxtaposed homologs and point to combinatorial interactions of its regions. They also suggest that chromosomal scaffold itself is an active contributor to compartmentalization of meiotic chromatin, thus potentially playing a role in the prevention of non-allelic recombination, the regulation of genome recognition and defense mechanisms, and the mediation of genome topology.
Table of Contents
Chapter 1: INTRODUCTION
1
Meiosis as a specialized type of cell division
2
Specifics of prophase I events across model organisms
3
C. elegans as a model system for studies of meiosis
6
Spatial organization of prophase I chromatin
8
Chromatin features as factors in regulation of meiotic processes
11
Heterochromatin in meiosis
13
Meiotic sex chromosome inactivation
16
Quality control of meiotic processes
18
RATIONALE
19
SIGNIFICANCE
20
Chapter 2: THE CONSEQUENCES OF THE APPEARANCE OF HETEROCHROMATIC DOMAINS ON UNIVALENTS FOR MEIOTIC PROCESSES
27
Introduction
28
Results
28
Discussion
31
Materials and methods
33
Chapter 3: SYNAPTONEMAL COMPLEX ASSEMBLY LEADS TO COMPARTMENTALIZATION OF HETEROCHROMATIC DOMAINS IN C. ELEGANS MEIOSIS
42
Introduction
43
Results
44
Discussion
67
Materials and methods
75
Chapter 4: SEX-SPECIFIC DIFFERENCES IN HETEROCHROMATIN DYNAMICS IN PROPHASE I OF C. ELEGANS
143
Introduction
144
Results
145
Discussion
147
Materials and methods
150
Chapter 5: SUMMARY AND FUTURE DIRECTIONS
156
REFERENCES
162
About this Dissertation
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