SWI/SNF chromatin remodelling complexes are one of the well-characterized cellular machineries capable of regulation of gene expression. Numerous lines of evidence indicate that SWI/SNF complexes are involved in a wide range of cellular processes and the maintenance of homeostasis whereas aberrant expression of those proteins contributes towards cancer development. Colorectal cancer remains one of the most clinically significant cancers due to its high incidence in developed countries and previous studies have demonstrated that SWI/SNF complexes are aberrantly regulated in a significant proportion of patients with this disease. However, whilst the sequence of molecular events leading to CRC has been well-established, the role of SWI/SNF chromatin remodelling complex ATPase subunits Brm and its paralogue Brg1 in the colorectal tumorigenesis remains elusive. The chromatin remodelling catalytic subunit Brm has been found to interact with the Notch pathway effectors ICD-22 and CBF-1 and also to be necessary for expression of the Wnt target gene CD44 and for Rb-mediated cell cycle arrest. In this PhD thesis, the potential of Brm to modulate Wnt-driven intestinal tumorigenesis was addressed. Initially, a murine model carrying constitutively deleted Brm was used to assess the consequences of this loss on homeostasis of the small intestinal and colonic epithelia. The effects of Brm deficiency were also examined in the context of Wnt-activated epithelium via conditional loss of Apc. Additionally, the effect of concomitant loss of Brm and Brg1 was addressed in the contexts of both normal homeostasis and aberrant Wnt signalling. The results presented here demonstrate that Brm plays an important role in the small intestine by regulating the distribution of proliferating cells and cell fate decisions mediated through Notch pathway effectors. Furthermore, Brm deficiency was found to modulate intestinal phenotype of Wnt activation through the attenuation of the Wnt transcriptional programme and the suppressed expression of the intestinal stem cell marker Olfm4. Thus while Brg1 has been widely characterized as a bone fide tumour suppressor, the function of Brm continues to remain elusive especially in the light of contrasting effects co-mediated by Brm on proliferation, differentiation and gene expression. Taken together, these results elucidate the tissue-specific role of Brm, the catalytic subunit of SWI/SNF chromatin remodelling complex, on both normal intestinal homeostasis and acute activation of Wnt pathway while the extent of these Brm-dependent effects depend upon the gradient of Wnt signalling throughout the epithelium of small and large intestine.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:646307 |
| Date | January 2014 |
| Creators | Krzystyniak, Joanna |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/73083/ |
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