Large offspring syndrome, a bovine model for the human loss-of-imprinting overgrowth syndrome Beckwith-Wiedemann

Beckwith-Wiedemann syndrome (BWS) is a pediatric overgrowth condition with increased likelihood to develop embryonic tumors. Children conceived with the use of assisted reproductive technologies (ART) have an increased frequency to have BWS compared to naturally-conceived individuals. Genomic imprinting is defined as parental allele-specific gene expression which is regulated by epigenetic modifications including DNA methylation. The molecular alterations associated with BWS have been mapped to human chromosome 11p15 region. This region harbors two imprinting loci which are known as imprinting center 1 (IC1) and IC2.;Currently, only associations exist between the 11p15 regions and BWS. No direct evidence is available to demonstrate how the alterations of 11p15 regions could lead to the variable BWS phenotypes. Importantly, no animal model exists that faithfully recapitulates the various phenotypes of BWS. In ruminants, there is a similar overgrowth condition that recapitulates the features of BWS which is known as large offspring syndrome (LOS). LOS is the result of ART in ruminants. A previous study in our laboratory found that the DNA methylation and allelic expression of imprinted genes in the IC1/IC2 are conserved between human and bovine. The goal of the current study is to determine if LOS in bovine displays the same epigenetic alterations of IC1 and IC2 as BWS in human.;In this thesis, chapter 1 will introduce genomic imprinting and discuss in detail how genomic imprinting is regulated by epigenetic modifications including DNA methylation, histone modifications, and non-coding RNAs. Chapter 1 will also introduce BWS, BWS-associated imprinted loci and will present associations between ART and BWS. LOS in bovine will also be described in chapter 1. Chapter 2, the research chapter, shows that similar loss-of-imprinting (LOI) of IC2 is observed in our LOS conceptuses generated with the use of ART. This chapter has been recently accepted in the Landes Bioscience Journal: Epigenetics.