The role of the Pygopus chromatin modulator in cell growth and division

Andrews, Phillip Gordon Patrick (2017) The role of the Pygopus chromatin modulator in cell growth and division. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

In adults, precisely regulated gene expression results in strict control of cell proliferation required for healthy tissues. Abnormal gene expression, on the other hand, can result in uncontrolled cell proliferation and tumor formation. Gene expression largely depends on changes to chromatin structure; it is remodeled in response to epigenetic stimuli to accommodate transcriptional activation and/or repression. Chromatin remodeling, therefore, is very broadly fundamental to normal and aberrant cellular function. Here, my research has focused on a key epigenetic effector that facilitates gene activation, called Pygopus 2 (Pygo2). Pygo2 functions primarily to link histone acetylation to active gene expression, by bridging transcription factors and modified histone proteins at gene promoters to histone acetyltransferases. In this thesis, I first examined the role of Pygo2 in the canonical Wnt signaling pathway and found that Pygo2 is transiently and specifically acetylated when bound to the activated -catenin complex. Acetylation of Pygo2 correlated with a displacement of nuclear Pygo2 to the cytoplasm, suggesting that acetylation of Pygo2 may control the recycling of -catenin complexes, following target gene activation. Upon examination of the broader role of Pygo2 beyond Wnt signalling, I found that it promotes ribosomal (r)RNA transcription within the nucleolus. In this context, Pygo2 was required for histone H4 acetylation at the rDNA promoter, suggesting a novel involvement of Pygo2 in rRNA transcription. Finally, using a whole genome approach, I discovered that Pygo2 acts as a pleiotropic chromatin effector, revealing a function for Pygo2 in gene expression required for segregation and bi-orientation of chromosomes during mitosis. Further analysis identified an interaction between Pygo2 and c-myc oncoprotein, suggesting that the chromatin effector Pygo2 may cooperate with c-myc, directing the expression of growth and division genes. Taken together, my findings suggest that in association with other important regulators of growth in cancer, Pygo2 facilitates gene expression by interpreting and relaying positive epigenetic marks on histones, which is essential to promote the expression of proliferation-related transcriptional programs.

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