Dissertation
Alternative polyadenylation as a genetic regulatory mechanism to bridge genome to phenome in the context of appetitive behaviors.
Washington State University
Doctor of Philosophy (PhD), Washington State University
2023
DOI:
https://doi.org/10.7273/000005002
Abstract
Energy is essential for life. On one end of the spectrum, over 1/3 of Americans live with obesity, which only occurs when excess energy is consumed and stored by the body. Obesity is comorbid with Type II diabetes, heart disease, and cancer, and is estimated to cost $147 billion United State dollars annually in economic expenditures. On the other end of the spectrum, more than 1/3 of cancer patients die from body wasting, not the cancer itself. One pertinent feature that contributes to body wasting is anorexia, or the loss of appetite. Even though the neuronal networks responsible for the control of energy balance and appetite are understood, how these networks are functionally adapted to environmental circumstances to maintain energy homeostasis is not yet well investigated. In this context, alternative polyadenylation is a post-transcriptional RNA processing mechanism that may functionally mediate environment x gene interactions. Over 70% of human transcripts undergo alternative polyadenylation, a process by which the selective use of canonical AAUAAA polyadenylation sites generate transcriptional diversity. The alternative use of polyadenylation sites is an important regulatory mechanism that establishes transcript maturation, stability, and localization, all of which are key aspects of gene expression in neuronal cells to coordinate behavioral responses.
This dissertation explores alternative polyadenylation in relation to appetite. The presented data indicate that 1) sex differences occur in a model of binge-like feedings in rats, 2) alternative polyadenylation is a post-transcriptional processing mechanism that is impacted by either diet-induced obesity or cannabis exposure in the brain’s endogenous appetite center, the hypothalamus, and 3) the alternative polyadenylation site on the 3′ untranslated region of the Timp2 transcript, identified as having distal alternative polyadenylation site use upregulation in diet-induced obesity, functionally mediates spinogenesis in hippocampal primary neurons. Collectively, this work contributes to a more comprehensive understanding of the neurobiological controls of appetite and elucidates alternative polyadenylation as a key post-transcriptional processing mechanism that modulates in response to appetitive state.
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Details
- Title
- Alternative polyadenylation as a genetic regulatory mechanism to bridge genome to phenome in the context of appetitive behaviors.
- Creators
- Julianna Nicole Brutman
- Contributors
- Gary A Wayman (Advisor)Emily Qualls-Creekmore (Advisor)Suzanne Appleyard (Committee Member)Michael Varnum (Committee Member)Zhihua Jiang (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 238
- Identifiers
- 99901019837301842
- Language
- English
- Resource Type
- Dissertation