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Characterising the role of Cbx3/HP1γ in normal intestinal homeostasis and tumourigenesis

Lio, Ka Ian 2015. Characterising the role of Cbx3/HP1γ in normal intestinal homeostasis and tumourigenesis. PhD Thesis, Cardiff University, School of Biosciences.
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Abstract

Epigenetic modifications are being increasingly recognised to contribute to colorectal cancer formation. Emerging evidence has demonstrated that HP1γ (coded by the gene Cbx3) has an important role in carcinogenesis by regulating several mechanisms, such as heterochromatin formation, gene silencing and DNA replication and repair. The aim of this study was to characterise the role of HP1γ in normal intestinal homeostasis and cancer progression. The Cbx3 gene was conditionally deleted in the murine small intestinal epithelium under normal intestinal homeostasis and in the context of aberrant Wnt signalling using transgenic mouse models. Furthermore, the long-term consequence of Cbx3 loss in Wnt-driven tumorigenesis was examined using a mouse model possessing a heterozygous mutation of the Apc gene. The results presented in this thesis demonstrate that Cbx3 has subtle effects on the histone epigenome, although these do not confer any noticeable manifestation in intestinal homeostasis. Upon aberrant Wnt-activation, Cbx3 loss resulted in prolonged survival potentially via attenuation of Wnt activation at the receptor level and RNA splicing defects. Furthermore, the long-term Cbx3 deficiency accelerates both Wnt-driven tumour development and progression, and reduces survival of male mice with heterozygous loss of Apc. Additionally, marked epigenetic alternations were observed in association patterns of HP1γ and the heterochromatin markers (H3K9me3 and H4K20me3) between wild-type and Apc-deficient intestines, suggesting the multifaceted roles of HP1γ in maintaining a gene-repressive environment in heterochromatin for normal intestinal homeostasis, and providing a gene permissive environment in euchromatin for carcinogenesis. The findings of this study demonstrate for the first time the functional versatility of HP1γ in intestinal homeostasis and tumorigenesis. Cbx3 plays a novel role in positive regulation of Wnt signaling and RNA splicing in the aberrant Wnt-activated intestine and a role in heterochromatin formation and gene silencing in long-term Wnt-activated tumorigenesis. These data contribute to the body of knowledge how colorectal cancer progresses and provide a critical foundation for further investigation of the role of HP1γ in Wnt signaling, RNA splicing, tumour progression, and its interaction with histone marks in mouse models of colorectal cancer.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Funders: Tenovus, Macau Government
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:56
URI: http://orca.cf.ac.uk/id/eprint/73537

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