Je-Hyun Yoon, Ph.D.
Research Project Leader 2020
Department of Biochemistry
Overview
Dr. Yoon’s research defined a novel post-transcriptional regulatory mechanism linking alcohol exposure to intestinal injury.
The project tested the hypothesis that ethanol (EtOH) activates the kinase MST1, which phosphorylates the RNA-binding protein AUF1, leading to degradation of microRNAs (miRNAs) that normally repress CYP2E1 expression. Loss of these miRNAs stabilizes CYP2E1 mRNA, increasing CYP2E1 protein levels and promoting oxidative stress, epithelial barrier dysfunction, and gut permeability.
These studies established a mechanistic framework linking RNA regulation to intestinal injury and liver disease in alcohol use disorders.
Specific Aims
- Define how MST1-mediated phosphorylation of AUF1 regulates degradation of CYP2E1-targeting miRNAs and stabilizes CYP2E1 mRNA
- Determine how miRNA-mediated regulation of CYP2E1 impacts intestinal epithelial growth, barrier function, and injury
Research Approach
The project integrated molecular, cellular, and in vivo approaches to dissect the MST1–AUF1–miRNA–CYP2E1 signaling axis. Primary intestinal cells, human intestinal cell lines, and intestinal organoids were used to define mechanistic pathways regulating miRNA stability and CYP2E1 expression. Genetic and pharmacologic manipulation of MST1 and AUF1, combined with miRNA overexpression or inhibition, allowed detailed analysis of post-transcriptional regulation. Mouse models of binge ethanol exposure were used to assess intestinal injury, gut permeability, and systemic consequences in vivo.
Use of the Center's Core Resources
Cell Models Core
- Generation of CRISPR-edited cell lines and organoids
Advanced Imaging Core
- Visualization of RNA localization and intestinal structure
Animal Models Core
- Ethanol-induced injury models and genetic mouse studies
Innovation
- Defines a novel post-transcriptional pathway linking alcohol exposure to intestinal injury
- Identifies AUF1 phosphorylation as a key regulator of miRNA stability
- Establishes miRNA degradation as a mechanism controlling CYP2E1 and oxidative stress
Impact and Outcomes
This work provides a conceptual advance in understanding how alcohol induces intestinal barrier dysfunction by revealing a previously unrecognized RNA regulatory mechanism. By linking MST1 signaling, AUF1 phosphorylation, and miRNA decay to CYP2E1-driven injury, this project identifies new therapeutic targets, including MST1 inhibitors and miRNA-based approaches.
Participation in the Center for Biomedical Research Excellence in Digestive & Liver Disease's program supported Dr. Yoon’s transition to independence and established a research program focused on RNA biology and gastrointestinal disease.
