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Dissertation
Exploring the genome: serendipitous discoveries in gene regulation and microproteins
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2025
DOI: 10.25820/etd.008144
Abstract
The cardiac voltage-gated sodium channel NaV1.5, encoded by SCN5A, is essential for proper cardiac conduction and its dysfunction is implicated in arrhythmias and heart failure. Through careful examination of bioinformatic and genomic data, this dissertation explores previously unrecognized regulatory mechanisms controlling NaV1.5 expression and function, revealing novel intersections between transcriptional and translational regulation, and mitochondrial function. In the first study, we identify a conserved alternative polyadenylation signal within SCN5A generates a truncated transcript isoform encoding an N-terminal fragment of NaV1.5 (NaV1.5-NT), which localizes to mitochondria and alters respiration through modulation of oxidative phosphorylation complexes. In the second study, we identify an ultra-conserved sequence element, present in most SCN(NaV)-family genes, that initiates translation in an alternative open reading frame and represses NaV1.5 translation in an ion-sensitive manner, suggesting a riboswitch-like mechanism. Furthermore, disruption of this element in SCN5A enhances NaV1.5 expression and alters cardiac conduction in mice. The third study identifies the true translational start codon of FNDC5, the gene encoding the exercise-inducible myokine irisin, resolving over a decade of controversy regarding its mode of expression in humans. Collectively, these findings uncover novel regulatory modalities controlling NaV1.5 expression which also generate SCN5A-derived microproteins. These discoveries offer new molecular insights into sodium channel biology, gene regulation, and microproteins, opening the door for future research aimed at exploring their therapeutic relevance.
Details
- Title: Subtitle
- Exploring the genome: serendipitous discoveries in gene regulation and microproteins
- Creators
- Nathan H Witmer
- Contributors
- Ryan L Boudreau (Advisor)Barry London (Committee Member)Ethan J Anderson (Committee Member)Eric B Taylor (Committee Member)Stefan Strack (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Molecular Medicine)
- Date degree season
- Summer 2025
- DOI
- 10.25820/etd.008144
- Publisher
- University of Iowa
- Number of pages
- xi, 166 pages
- Copyright
- Copyright 2025 Nathan H Witmer
- Language
- English
- Date submitted
- 07/17/2025
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 143-166).
- Public Abstract (ETD)
Through examination of publicly available data, this research identifies new ways our genes are controlled and how tiny proteins, called microproteins, can play surprising roles in heart function. The heart relies on a protein called NaV1.5 to generate electrical signals that keep it beating correctly. In this thesis, I discovered two new ways that cells control how much NaV1.5 they make and even uncovered new proteins hiding within its gene. First, I found that the SCN5A gene can produce a small version of the NaV1.5 protein. This version travels to the mitochondria, the cell s energy center, where it changes how much energy is made in heart cells. Second, I identified a genetic switch that controls how much NaV1.5 is made, depending on the amount of certain ions inside the cell. When this switch is turned off in mice, more NaV1.5 is made, and their heart s electrical signals change. In a separate project, I helped solve a decadelong mystery about how the exercise hormone irisin is made in humans. Together, these findings highlight how much is hiding within our genetic code, opening the door to potential new treatments for heart diseases, by targeting these newly discovered genetic features.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984948641402771
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