Title: Genomic imprinting and the epigenetic control of mammalian development and human disease
Epigenetic modifications play key roles in chromosome architecture and integrity, chromatin structure and gene activity and repression. One of the key challenges in contemporary genome biology is to understand the relationship between the epigenome and the underlying DNA sequence with which it interacts. Genomic imprinting is a normal epigenetic regulatory process causing genes to be expressed from only one of the two parental chromosome homologues according to their parental origin. Imprinted genes function prenatally and postnatally in a range of developmental pathways controlling normal organogenesis, growth and metabolism. Perturbations of genomic imprinting are responsible for several disorders exhibiting parental-origin effects in their patterns of inheritance. Abnormal imprinting has also been implicated in a wide range of different cancers. More recently, genome-wide association studies that have considered the parent-of-origin of variants have identified novel associations between imprinted domains and complex diseases.
The mouse is a useful model for the analysis of defective imprinting mechanisms and the phenotypic contributions of genes whose dosage is perturbed in imprinting disorders. Recent advances have included the identification of mutations in trans-acting factors in mouse and human that are required for the stable maintenance of epigenetic states at multiple imprinted domains, and whose further analysis is likely to provide novel insights into molecules that integrate genomic with epigenomic information. In recent years, data have emerged identifying discordance of imprinting between mouse and man, polymorphic imprinting between different individuals and tissue and cell-specific imprinting within individuals. This suggests that epigenetic control modulating mono-allelic and biallelic expression at imprinted loci might be a dynamic process with the potential to act as a regulatory mechanism controlling gene dosage in different developmental contexts. This potential plasticity of epigenetic control at imprinted domains may contribute to their vulnerability, and help contribute to our understanding of the mechanisms and consequences of epimutation of the genome in a wider context.
