The H3.3 G34W mutation disrupts the balance between H3K27 and H3K36 methylation to corrupt cellular identity in giant cell tumor of bone and an oncogenic role for ASH1L in lung adenocarcinoma and possibly multiple human cancers
Abstract/Contents
- Abstract
- The precise temporal and spatial coordination of histone lysine methylation dynamics across the epigenome regulates virtually all DNA-templated processes. A large number of histone lysine methyltransferase (KMT) enzymes catalyze the various lysine methylation events decorating the core histone proteins. Mutations, genetic translocations and altered gene expression involving these KMTs are frequently observed in cancer, developmental disorders and other pathologies. Therapeutic compounds targeting specific KMTs are currently being tested in the clinic, although overall drug discovery in the field is relatively under-developed. In chapter 1, we review the biochemical and biological activities of histone KMTs and their connections to human diseases, focusing on cancer. We also discuss the scientific and clinical challenges and opportunities in studying KMTs. In chapter 2, we characterize the role of the oncogenic H3.3 G34W mutation in Giant Cell tumor of the bone. To do so, we have created a novel cellular model of the disease using primary human mesenchymal stem cells. Using this model, along with biochemical assays, we determine the causal mechanistic consequences of the H3.3 G34W mutation and identify a novel potential mechanism for crosstalk between epigenetic modifications. In chapter 3, we discuss the role of the ASH1L in human cancers. We find that chromosomal amplification or gain of ASH1L is a highly recurrent event in many tumor types, including Lung Adenocarcinoma (LUAD). We interrogate the specific mechanisms involved in tumorigenesis of Lung Adenocarcinoma (LUAD) using biochemical methods as well as human LUAD cell lines to determine the mechanisms by which ASH1L contributes to tumorigenesis. We also utilize murine models of LUAD to determine the in vivo contributions of ASH1L to the process of tumorigenesis, and find that ASH1L plays a critical role in genetic models of LUAD. In chapter 4, we present a broader view of the field of cancer epigenetics in the context of H3K27 and H3K36 methylation. We highlight several outstanding questions of importance in the field, and nascent opportunities to answer them. We also discuss clinical opportunities on the horizon and the relationship they might have with these outstanding questions.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Husmann, Dylan Graham |
|---|---|
| Degree supervisor | Gozani, Or Pinchas |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Dixon, Scott James, 1977- |
| Thesis advisor | Winslow, Monte |
| Thesis advisor | Wysocka, Joanna, Ph. D. |
| Degree committee member | Dixon, Scott James, 1977- |
| Degree committee member | Winslow, Monte |
| Degree committee member | Wysocka, Joanna, Ph. D. |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Dylan Husmann. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/fy030yz2454 |
Access conditions
- Copyright
- © 2021 by Dylan Graham Husmann
- License
- This work is licensed under a Creative Commons Attribution Share Alike 3.0 Unported license (CC BY-SA).
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