Genomic Imprinting

by Wilkins, Jon F., Ph.D.

• ISBN13: 9780387775753
• ISBN10: 0387775757
• Edition: 1st
• Format: Hardcover
• Copyright: 2008-01-31
• Publisher: Landes Bioscience

Summary

Genomic imprinting refers to a recently discovered phenomenon in which the expression pattern of an allele depends on whether that allele was inherited from the mother or the father. This difference in expression strategy correlates with differences in the epigenetic state of the two alleles. These epigenetic differences include DNA methylation at CpG dinucleotides, as well as modifications on the histones associated with the locus. In the simplest possible cases, the promoter region of the imprinted gene is methylated during oogenesis, but not spermatogenesis (or vice versa). This methylation (and its accompanying histone modifications) results in inactivation of the modified allele. Of course, most imprinted genes do not fall into this simplest case. The goal of this book is neither to provide a basic introduction to imprinting, nor to provide a comprehensive survey of the current state of the field (which would necessarily span multiple books). Rather, the book covers on some of the more recent advances, with the goal of drawing attention to some of the emerging subtleties and complexities associated with imprinted genes.

Table of Contents

DNA Methylation Reprogramming in the Germ Line	p. 1
Introduction	p. 1
Methylation of Repeats and Genome Stability	p. 3
Demethylation in the Germ Line	p. 3
De Novo Methylation in the Developing Gametes	p. 8
Fate of Methylation Differences Inherited from the Gametes in the Early Embryo	p. 10
Methylation Enforces Transcriptional Silencing and Suppresses Recombination	p. 11
Repeats Attract Methylation, while Transcription Factors Block It	p. 12
Conclusions	p. 12
Control of Imprinting at the GNAS Cluster	p. 16
Background	p. 16
Extent of the Region	p. 17
Transcripts at the Gnas Locus	p. 18
Proteins Encoded at the Gnas Complex Locus	p. 18
Function of Proteins Encoded at the Gnas Locus	p. 18
Imprinting Centers	p. 19
The Exon 1A DMR Controls the Expression of Gnas	p. 21
The Nespas DMR is the Principal ICR in the Gnas Cluster	p. 21
Interaction between the Nespas DMR and the Exon 1A DMR	p. 22
The Role of Nespas	p. 23
The Role of the Exon 1A DMR	p. 23
Conclusions	p. 24
The GNAS Locus and Pseudohypoparathyroidism	p. 27
Introduction	p. 27
Inactivating Gs¿ Mutations and Multiple Hormone Resistance: PHP-Ia	p. 29
Role of Tissue-and Parental Origin-Specific Gs¿ Expression in Hormone Resistance	p. 30
Mutations Affecting the Imprinting Control Regions of GNAS and PTH-Resistance: PHP-Ib	p. 32
Conclusion	p. 36
Imprinted Genes, Postnatal Adaptations and Enduring Effects on Energy Homeostasis	p. 41
Introduction	p. 41
Imprinted Gene Syndromes and Obesity	p. 41
Genetic Evidence for Parent-of-Origin Effects on Obesity	p. 43
Imprinted Gene Action in the Hypothalamus	p. 43
Imprinted Gene Action in Adipose Tissues	p. 44
The Gnas Locus	p. 46
The Role of Gs¿ in Energy Homeostasis	p. 48
XL¿s in Postnatal Adaptations and Metabolism	p. 53
Mutations of the GNAS Locus in Human Neonatal Physiology and Adult Energy Homeostasis	p. 54
The 'Conflict Hypothesis' and Beyond	p. 55
Concluding Remarks	p. 56
What are Imprinted Genese Doing in the Brain?	p. 62
Abstract	p. 62
Imprinted Genes and the Brain	p. 62
Summary Evidence for a Role for Imprinted Genes in Brain Function	p. 63
Characteristics of Brain-Expressed Imprinted Genes	p. 63
Imprinted Gene Effects on Brain Development	p. 64
Imprinted Gene Effects on Behavior	p. 65
Through What Mechanisms Might Imprinted Genes Affect (Adult) Behavior?	p. 66
Imprinted Genes in the Adult Brain	p. 67
What Adult Behaviors Will Imprinted Genes Influence?	p. 67
Genomic Imprinting and Human Psychology: Cognition, Behavior and Pathology	p. 71
Abstract	p. 71
Genomic Imprinting in Human Cognition and Behavior	p. 71
Imprinted Syndromes, Behavioral Phenotypes and Neuropsychological Research	p. 76
Conclusion	p. 80
Genomic Imprinting in Plants	p. 89
What is Genomic Imprinting?	p. 89
Evolution of Genomic Imprinting	p. 89
Genomic Imprinting in Plants	p. 90
Imprinting Regulation at the Maternally Expressed MEDEA Locus in Arabidopsis thaliana	p. 91
Imprinting Regulation at the Maternally Expressed FWA Locus in Arabidopsis thaliana	p. 93
Imprinting Regulation at the Paternally Expressed PHE1 Locus in Arabidopsis thaliana	p. 93
Imprinting Regulation at the Maternally Expressed FIS2 Locus in Arabidopsis thaliana	p. 93
Differentially Methylated Domains (DMDs) and Imprinting Regulation in Plants	p. 93
Emerging Models for Imprinting Regulation in Plants	p. 94
Imprinted Genes and Human Disease: An Evolutionary Perspective	p. 101
Abstract	p. 101
Do Disorders Linked to Imprinted Genes Share a Common Motif?	p. 102
Growth and Resource Acquisition	p. 103
Post-Natal Behavior	p. 107
Cancer	p. 108
Are Imprinted Genes Particularly Fragile?	p. 108
Mutations	p. 109
Epimutations	p. 111
Uniparental Disomies	p. 112
Implications for the Prevention and Treatment of Human Disease	p. 112
Evolutionary Theories of Imprinting-Enough Already!	p. 116
Abstract	p. 116
Introduction	p. 116
What Needs to be Explained?	p. 117
The Etiquette of Proposing a New Theory of Imprinting	p. 119
Conclusion	p. 121
Index	p. 123
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