A cis-regulatory lexicon of DNA motif combinations mediating cell type-specific gene regulation
Abstract/Contents
- Abstract
- The role of the DNA sequence in protein-coding genes has been widely established due to the obvious functional relevance and well-defined relationships between DNA variation and protein sequence. However, most disease-associated variants are not in protein-coding sequences. This has led to much investigation of non-coding variation as it relates to protein-coding gene regulation. Critically, non-coding regulatory elements within DNA are intricately linked to cell type-specific protein-coding gene expression. This dissertation contributes to the goal of uncovering the underlying cis-regulatory logic of non-coding DNA sequences driving cell type-specific gene expression in homeostasis and disease. Cell type-specific non-coding cis-regulatory elements are known to drive important gene expression programs. However, it is still unclear what combinatorial DNA sequences underlie cell type-specific gene regulatory mechanisms. The objective of this dissertation is to progress our understanding of cis-regulatory logic through integration of genome-wide regulatory maps followed by modeling of combinatorial DNA motif logic in cis-regulatory modules regulating cell type-specific gene expression programs and focused identification of functional regulatory DNA motif combinations (DMCs) in homeostasis and complex disease. In Chapter 2, I generate epigenomic and transcriptomic profiles of 15 primary human cell types and perform integrated analysis to define cell type-specific open chromatin peak-long range looped-expressed target gene transcripts (PLTs). I then incorporate disease-associated single nucleotide variants (SNVs) from the NHGRI GWAS catalog and Genotype-Tissue Expression (GTEx) data to link SNVs enriched in cell type-specific PLTs to putative target genes. In Chapter 3, I model the genomic information necessary to derive cis-regulatory modules linked to cell type-specific gene expression programs and nominate transcription factor (TF) DMCs underlying cell type-specific regulatory logic. Finally, in Chapter 4, I validate DMC logic in four primary human cell types and identify cancer-specific regulatory logic in human squamous cell carcinoma and melanoma cells. The findings and approaches described in this dissertation add to the existing annotation of functional combinatorial TF motif logic and help build a framework for future studies of cis-regulatory logic.
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 | Donohue, Laura Kaitlin Hill |
|---|---|
| Degree supervisor | Khavari, Paul A |
| Thesis advisor | Khavari, Paul A |
| Thesis advisor | Baker, Julie, (Professor of genetics) |
| Thesis advisor | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Thesis advisor | Montgomery, Stephen, 1979- |
| Degree committee member | Baker, Julie, (Professor of genetics) |
| Degree committee member | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Degree committee member | Montgomery, Stephen, 1979- |
| Associated with | Stanford University, Department of Genetics |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Laura Kaitlin Hill Donohue. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/fs026ky0561 |
Access conditions
- Copyright
- © 2021 by Laura Kaitlin Hill Donohue
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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