Genomic imprinting refers to the parent-of-origin specific monoallelic expression of a gene. Imprinted genes are often clustered in the genome and their expression is regulated by an imprinting centre (IC). ICs are regions of DNA that propagate the parental specific regulation of gene expression, which are usually characterized by differential DNA methylation, histone marks and the presence of non-coding RNAs. Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with the dysregulation of imprinted gene expression on human
chromosome band 11p15.5. The 11p15.5 imprinted region has two imprinting centres, IC1 and IC2. IC1 is telomeric and regulates the imprinted expression of the genes H19 and IGF2. IC2 is ~700kb centromeric and is associated with a cluster of nine imprinted genes including CDKN1C, KCNQ1 and an imprinted non-coding RNA associated with IC2, KCNQ1OT1. Loss of differential DNA methylation at IC2 is seen in 50% of patients with BWS with loss of
imprint of the non-coding RNA KCNQ1OT1 and associated with a decreased expression of the
putative tumour suppressor CDKN1C. Patients with BWS also have a thousand-fold increased
risk of pediatric cancer. The focus of this thesis involves investigation of dysregulation of
imprinting in three groups of BWS patients. Firstly, I show that BWS patients with alveolar
rhabdomyosarcoma have constitutional loss of methylation at IC2 and biallelic expression of
KCNQ1OT1. Secondly, loss of methylation at IC2 has been previously associated with female
monozygotic twins discordant for BWS. In male monozygotic twins with BWS, however, the
molecular lesions reflect the molecular heterogeneity seen in BWS singletons. Thirdly, BWS
patients associated with translocations and inversions that have breakpoints within the KCNQ1
gene near IC2 show regional gain of DNA methylation around the breakpoint and decreased
expression of CDKN1C. Therefore, using a rare collection of BWS patients, I have attempted to
determine the various roles of the imprinting centres IC1 and IC2 and their involvement in
tumourigenesis, monozygotic twinning and structural chromosomal rearrangements causing
BWS.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/19296 |
| Date | 03 March 2010 |
| Creators | Smith, Adam Campbell |
| Contributors | Weksberg, Rosanna |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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