Date of Award
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular, Molecular and Biomedical Sciences
First Advisor
James M. Stafford
Second Advisor
Amanda E. Hernan
Abstract
Pogo transposable element derived with ZNF domain (POGZ) is a protein that plays a role in DNA repair pathways and is implicated in neurodevelopment. For example, POGZ is a high confidence marker for autism spectrum disorder (ASD), and pathogenic heterozygous de novo variants in POGZ have been shown to cause White-Sutton syndrome (WHSUS), a disorder characterized by cognitive dysfunction, developmental delays, and ASD. Other studies suggest a role in cancer. However, the precise molecular mechanism by which POGZ plays a role in these normal and disease-linked processes is poorly understood. This dissertation explores two potential roles for POGZ, one in transcription and the other in DNA damage repair. First, preliminary data from our group found that POGZ associates with polycomb repressive complex 1 (PRC1) a known epigenetic regulator in the developing brain, repressing stem cell differentiation and developmental genes in neural lineages. While we confirmed that POGZ itself is a repressor of transcription, we were not able to clearly demonstrate that repression relied on the core PRC1 subunit, RING1B, in a forced recruitment assay. Despite challenges directly linking POGZ and PRC1, we were able to show that three ASD-linked POGZ mutants yielded varying levels of de-repression, likely due to the locations of the mutations spanning different domains of POGZ. As POGZ has a DNA binding domain and localizes to chromatin with distinct epigenetic features, we postulate that these mutations disrupt either POGZ recruitment to chromatin or its ability to act as a chromatin effector leading to aberrant transcriptional states yielding diverse neurodevelopmental phenotypes like ASD or White-Sutton syndrome. Second, we built on studies indicating that POGZ is a regulator of DNA repair via its mediation of HP1γ, linking POGZ to oncogenesis as it is known that dysregulation of DNA damage response (DDR) pathways can lead to cancer. Further, POGZ deficiency has been linked to cell cycle disruption in cancer cells where it is also co-expressed with cyclins. Taken together, these data point to a system wherein POGZ can affect gene expression via PRC1.6 as well as regulate DNA repair, thus having a far reaching, master driver role in neurodevelopment and potentially cancer. Because of this, we hypothesized that POGZ could be targeted for more effective treatment of gliomas that arise out of dysregulation of stem cell differentiation or the DDR. To test this, POGZ was knocked down in glioma cell lines. Surprisingly, this alone was not sufficient to induce DNA damage, while other agents functioned as positive controls demonstrating dose-dependent DNA double strand breaks (DSBs) in a cell line with an innately high DSB burden. Taken together, these data describe POGZ as a regulator of neurodevelopment and genomic stability that can be leveraged for therapeutic benefit. In the future, we hope to determine the mechanism through which POGZ causes neurodevelopmental dysregulation and further assess POGZ as a potential biomarker for brain cancer patients.
Language
en
Number of Pages
153 p.
Recommended Citation
Wolf, Trevor Hamilton, "Understanding POGZ Across Neurodevelopment and DNA Repair" (2024). Graduate College Dissertations and Theses. 1814.
https://scholarworks.uvm.edu/graddis/1814