The Role of Histone Variants, Histone Modifications, and Germline Transcription on Imprint Establishment and Epigenetic Inheritance in Caenorhabditis elegans Public

Abstract

The Role of Histone Variants, Histone Modifications, and Germline Transcription on Imprint
Establishment and Epigenetic Inheritance in Caenorhabditis elegans
By Jackelyn Kay Arico
Epigenetic information such as parental imprints can be transmitted along with genetic
information through the germ line from parent to offspring. Recent reports show that histone
modifications marking developmentally regulated loci can be transmitted through sperm as a
component of this information transfer. How the information that is transferred is established in
the parent and maintained in the offspring is poorly understood. Our lab had previously described
a form of imprinted X inactivation in C. elegans where dimethylation on histone 3 at lysine 4
(H3K4me2), a mark of active chromatin, is excluded from the paternal X chromosome (Xp)
during spermatogenesis and persists through early cell divisions in the embryo. We first
examined the role of histone variants and histone modifications in imprint establishment.
Although the histone variants examined were not required for imprint establishment, and the
histone modifications characterized were not unique to the Xp, these studies reinforced the
observation that the Xp (unlike the maternal X or any autosome) is largely transcriptionally
inactive in the paternal germ line. Based on this observation, we hypothesized that transcriptional
activity in the parent germ line may influence epigenetic information inherited by and maintained
in the embryo. We observed that chromatin modifications and histone variant patterns assembled
in the germ line can be retained in mature gametes. Furthermore, despite extensive chromatin
remodeling events at fertilization, the modification patterns arriving with the gametes are retained
in the early embryo. Using transgenes, we observed that expression in the parental germline
correlates with differential chromatin assembly that is replicated and maintained in the early
embryo. Expression in the adult germ cells also correlates with more robust expression in the
somatic lineages of the offspring. These results suggest that chromatin environments established
in the parental germ lines may provide a potential mechanism for the inheritance of parent of
origin epigenomic content that can be maintained and heritably affect gene expression in the
offspring.

Table of Contents

TABLE OF CONTENTS

Chapter 1:

Introduction 1
Chromatin and Histone Modifications 2
Histone Variants 7
DNA Methylation 11
Imprinting 13
Meiotic Sex Chromatin Inactivation 16
Sperm Chromatin 17
Transgenerational Inheritance 19
C. elegans 20
Rationale 23
Significance 25
Chapter 2: Examining the Role of Histone Variants and Histone Modifications in
Imprint Establishment in C. elegans 38
INTRODUCTION 39
RESULTS 44
Characterization of Histones H3 Variants in the Germline and Early Embryo 44
Examination of Histone Modifications in the Germline and Early Embryo 48
Active Histone Modifications H3K4me3, H3K18Ac and H3K36me3 48
Ubiquitination 49
Unmodified H3K4 51
H3K27 Methylation 51
H3K9 Tri-Methylation 52
DISCUSSION 53
MATERIALS AND METHODS 56
Chapter 3: Epigenetic Patterns Maintained in Early C. Elegans Embryos
Can Be Established by Gene Activity in the Parental Germ Cells 74
INTRODUCTION 75
RESULTS 79
Sex Body Formation and Imprint Establishment are X DNA Autonomous 79
Mature Sperm Chromatin Retains Epigenetic Information that Correlates with Spermatogenic Transcription 81
Transcriptional Activity in Adult Correlates with Chromatin Status in the Embryo85
DISCUSSION 93
MATERIALS AND METHODS 99
Chapter 4: Transcription of Imprinted Non-Coding RNAs in Mammalian
Spermatogenesis 125
INTRODUCTION 126
RESULTS 131
DISCUSSION 133
MATERIALS AND METHODS 136
Chapter 5: Future Directions 140
MODEL 141
FUTURE DIRECTIONS 142
Chip-Seq of Histone Modifications at Gene-by-Gene Resolution 142
Candidate RNAi Screen for Modifiers of the Imprint 145
CONCLUSIONS 148
REFERENCES 152

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Biochemistry, Cell & Developmental Biology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Genetics Biology, Cell
Mot-clé	epigenetics H3K4 imprint inheritance histone C. elegans
Committee Chair / Thesis Advisor	Kelly, William G, Emory University
Committee Members	Lucchesi, John, Emory University Powers, Maureen, Emory University Vertino, Paula M, Emory University L'Hernault, Steven, Emory University

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