All ETDs from UAB

Advisory Committee Chair

Quamarul Hassan

Advisory Committee Members

Amjad Javed

Chad Petit

Thomas Ryan

Rui Zhao

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Feedback loops between cellular cues and changes in gene expression mediate the interactions between a multitude of regulatory events that promote development and cancer. Vesicular trafficking is an important process in carrying out signaling events by transporting receptors and ligands to and from the cell surface. GBF1 and BIG1 are large guanine-exchange factors (GEFs) that activate GTPase mediated shuttling of cargo through the Golgi apparatus. This dissertation demonstrates that GBF1 localizes to the cytoplasmic membrane in glioblastoma multiform cells to maintain cell shape and promote migration. Reports have shown that BIG1translocates to the nucleus is hepatocyte carcinoma cell lines in response to serum starvation. Evidence that BIG1 functions in the nucleus includes direct binding to Dpy30, a positive regulator of gene expression. Dpy30 is an integral subunit of the Set1-Mll Histone 3 Lysine 4 (H3K4) methyltransferase complex. Expression of Dpy30 and its binding partner Ash2l are both upregulated in cancer cells by the oncogenic transcription factor c-Myc. This dissertation dissects the role of Dpy30 hyperactivation in Myc-dependent cancers and identifies Dpy30 as a potential therapeutic target for certain cancers. Dpy30 inhibition leads to a decrease in chromatin accessibility around Myc target genes. This supports a mechanism for co-regulation between methyltransferase complexes and ATPase-dependent chromatin remodelers like the BAF complex. BAF complexes are large molecular machines comprised of 15 different subunits that have tissue and context specific assemblies. This dissertation also shows that BAF45A, a subunit of the BAF complex, mediates chromatin accessibility and gene expression in mineralized tissues including osteoblasts of the bone and odontoblasts of the tooth. Collectively, this research draws a connection between multifactorial chromatin regulation and Golgi trafficking. In addition, these studies demonstrate the importance of dissecting novel cellular mechanisms for the purpose of developing efficient therapeutic strategies across different diseases.

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