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Dissertation
A novel interaction between long non-coding RNA lncTCF7 and SND1 modulates the gene regulation activity of the SWI/SNF complex
Doctor of Philosophy (Ph.D.), Drexel University
May 2023
DOI:
https://doi.org/10.17918/00001647
Abstract
Mammalian genomes have widespread transcription, with over two-thirds of the genome transcribed to yield thousands of noncoding transcripts. Among noncoding RNAs, long non-coding RNAs (lncRNAs) have emerged as critical players in gene regulation. LncRNAs are RNA transcripts longer than 200 nucleotides with no protein-coding capacity, and their expression is often specific to disease states, developmental stages, and tissue types. LncRNAs are versatile molecules that form RNA-RNA, RNA-DNA, and RNA-protein interactions and modulate diverse cellular functions, including but not limited to chromatin remodeling, transcription regulation, and mRNA decay and stability. The lncRNA lncTCF7 is key in regulating cancer progression in multiple cancer types. The proposed model of lncTCF7's function suggests that lncTCF7 activates gene expression by recruiting the SWI/SNF complex to the promoter of the gene TCF7 to activate WNT signaling, which is a commonly deregulated pathway in malignant cancers. However, the mechanism behind this recruitment process remains unclear, and lncTCF7-specific binding partners are unknown. Using RNA-pulldown and quantitative mass spectrometry, we identified a novel interacting protein partner for lncTCF7, SND1, a multifunctional RNA binding protein that can also function as a transcription co-activator. Knockdown analysis of lncTCF7 and SND1 revealed they are both required to upregulate TCF7, an important WNT signaling pathway transcription regulator. We also investigate the mechanism behind this gene regulation using chromatin immuno-precipitation and find that both SND1 and lncTCF7 recruit other factors to the promoter of TCF7. Specifically, lncTCF7 recruits SND1, while SND1 recruits the SWI/SNF chromatin remodeling complex, and these functions in tandem activate the expression of TCF7. Finally, using structural probing and a lncTCF7 subdomain-specific RNA pulldown, we highlight the potential binding region for SND1 in the 3'-end domain of lncTCF7. Overall, this study highlights the critical roles played by lncRNAs in regulating gene expression and provides new insights into the complex network of interactions that underlie this process.
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Details
- Title
- A novel interaction between long non-coding RNA lncTCF7 and SND1 modulates the gene regulation activity of the SWI/SNF complex
- Creators
- Allison Alizabeth Yankey
- Contributors
- Srinivas Somarowthu (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xi, 160 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991020668807804721