Dissection of cancer-specific cis and trans-regulatory elements
Abstract/Contents
- Abstract
- Cancer is one of the leading causes of death worldwide. Although the 2% of the human genome that encodes proteins has been extensively studied, much remains to be learned about the noncoding genome and gene regulation in cancer. Genes that specify cells and cell states are actively regulated by transcription factor (TF) proteins acting on DNA regulatory elements that are scattered over the vast noncoding genome and exert long-range influences. This work charts the discovery and characterization of noncoding regulatory elements and provides key insights into the extent to which they contribute to oncogenesis. In this work, we profiled the chromatin accessibility landscape of over 400 primary tumors spanning 23 cancer types with The Cancer Genome Atlas (TCGA). We identified specific cis- and trans-regulatory elements that identify these diverse cancers. We discovered a new class of mutations in non-coding regulatory elements that lead to dramatic changes in chromatin accessibility in primary human cancer. We further extended and expanded the resolution of profiling chromatin accessibility to single cells for both solid and liquid primary tumor microenvironments. We developed a single cell multi-omic framework for deconvolution of abnormal molecular phenotypes spanning DNA accessibility, gene expression and surface protein abundance. With the growing scale of single cell chromatin accessibility datasets, we developed a scalable and comprehensive single cell ATAC-seq analysis software package enabling researchers world-wide to analyze this large data type with minimal computing resources. Furthermore, we leveraged both bulk and single cell chromatin accessibility profiling and characterized genotype-specific chromatin states of tumor and metastatic progression in lung adenocarcinoma. We developed a novel single cell multi-omic method for measuring sgRNA genotypes and chromatin accessibility to functionally interrogate trans-regulatory proteins. Lastly, we improved the efficiency of HiChIP, a protein-associated chromosome conformation assay, to work with noncoding RNAs and identified novel RNA-focused 3D interactions. The results of this work led to the development of novel genomic methods that were utilized to provide novel insights into the mechanisms of gene regulation in many cancer types that can be used for targeted therapies, minimal residual disease monitoring and early detection screening.
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 | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Granja, Jeffrey Michael |
|---|---|
| Degree supervisor | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Degree supervisor | Greenleaf, William James |
| Thesis advisor | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Thesis advisor | Greenleaf, William James |
| Thesis advisor | Bintu, Lacramioara |
| Thesis advisor | Engreitz, Jesse |
| Degree committee member | Bintu, Lacramioara |
| Degree committee member | Engreitz, Jesse |
| Associated with | Stanford University, Biophysics Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jeffrey Michael Granja. |
|---|---|
| Note | Submitted to the Biophysics Program. |
| Thesis | Thesis Ph.D. Stanford University 2020. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Jeffrey Michael Granja
- License
- This work is licensed under a Creative Commons Attribution Non Commercial No Derivatives 3.0 Unported license (CC BY-NC-ND).
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