ORCID
https://orcid.org/0000-0002-7924-0052
Date of Award
12-18-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The regulation of messenger RNA (mRNA) splicing, stability, and translation efficiency are major modes for controlling gene expression – which is essential for life. RNA-binding proteins (RBPs) and microRNAs (miRNAs) are trans-acting factors that bind to cis-elements influencing the stability and translation of the mRNA transcript. AU-rich elements (AREs) are cis-elements that are targeted by AU-rich element binding proteins (ARE-BPs). Here, I show a novel role for AREs and AU-rich element binding protein 1 (AUF1) during alternative splicing and report on interactions of RBPs and miRNAs to design a new treatment for breast cancer by interrupting these interactions in the 3’UTR. Using a reporter-based approach we show that AREs can impact splice-site selection based on their location in the 3’UTR. Using CRISPR engineered AUF1 hypomorph and AUF1 isoform add-back cell lines we show AUF1 and AREs impact alternative splicing endogenously, and that AUF1 isoforms regulate RNA at different levels. Additionally, through our knowledge of miRNA and AUF1 interactions, we design antisense oligos (ASOs) to target motifs in the 3’UTR of BRCA1 to rescue BRCA1 haploinsufficiency.
Language
English (en)
Chair and Committee
Sergej Djuranovic
Committee Members
Andrew Yoo; Hani Zaher; Joseph Dougherty; Kristen Kroll
Recommended Citation
Jungers, Courtney Fay, "Gene Expression Regulation by AU-Rich Elements and AU-Rich Element Binding Proteins" (2024). Arts & Sciences Electronic Theses and Dissertations. 3352.
https://openscholarship.wustl.edu/art_sci_etds/3352