GSBS Dissertations and Theses

Approval Date

9-3-2014

Document Type

Doctoral Dissertation

Academic Program

Biochemistry and Molecular Pharmacology

Department

Biochemistry and Molecular Pharmacology

First Thesis Advisor

Sean P. Ryder, PhD

Keywords

Fatty Acids, Gene Expression Regulation, RNA, RNA-Binding Proteins, Stem Cells

Subjects

Dissertations, UMMS; Fatty Acids; Gene Expression Regulation; RNA; RNA-Binding Proteins; Stem Cells

Abstract

All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control transcription and activate second-­‐messenger systems. In bacteria, metabolites also affect post-­‐transcriptional regulatory mechanisms, but there are only a few isolated examples of this regulation in eukaryotes. Here, I present evidence that RNA-­‐binding by the stem cell translation regulator Musashi-­‐1 (MSI1) is allosterically inhibited by 18-­‐22 carbon ω-­‐9 monounsaturated fatty acids. The fatty acid binds to the N-­‐terminal RNA Recognition Motif (RRM) and induces a conformational change that prevents RNA association. Musashi proteins are critical for development of the brain, blood, and epithelium. I identify stearoyl-­‐CoA desaturase-­‐1 as a MSI1 target, revealing a feedback loop between ω-­‐9 fatty acid biosynthesis and MSI1 activity. To my knowledge, this is the first example of an RNA-­‐binding protein directly regulated by fatty acid. This finding may represent one of the first examples of a potentially broad network connecting metabolism with post-­‐transcriptional regulation.

DOI

10.13028/M2VC8Q

Rights and Permissions

Copyright is held by the author, with all rights reserved.

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