# Functional Characterization of the Pseudouridine Synthase PUS10

> **NIH NIH F31** · YALE UNIVERSITY · 2021 · $30,917

## Abstract

PROJECT SUMMARY
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract affecting
millions of individuals worldwide. The majority of patients afflicted with IBD exhibit chronically active disease
symptoms, representing a clear unmet need to advance our understanding of IBD pathology and identify new
therapeutic targets. Multiple genome-wide association studies have identified pseudouridine synthase 10
(PUS10) as a susceptibility gene for IBD. PUS10 encodes an enzyme responsible for installing the modified
nucleotide pseudouridine (Ψ) in a subset of human tRNAs and is likely to target mRNA as well. Individuals with
IBD-associated PUS10 alleles exhibit decreased expression, suggesting that loss of PUS10-dependent Ψ in
one or more of its target RNAs underlies its role in IBD. However, the functional consequences of PUS10-
dependent pseudouridylation are unknown. Notably, my preliminary analysis demonstrates that loss of PUS10
activity initiates an epithelial-to-mesenchymal transition (EMT), a pro-fibrotic cellular process that is
dysregulated in IBD and known to contribute to the pathogenesis of other chronic inflammatory disorders. My
work seeks to elucidate the molecular function of PUS10-dependent pseudouridylation and pinpoint its roles in
EMT initiation.
Ψ has profound impacts in both coding and non-coding RNA, affecting RNA processing, decay, and
translation—establishing a broad potential for PUS10 to regulate gene expression. I will begin to characterize
the role of PUS10 by comprehensively mapping and quantifying PUS10-dependent Ψ transcriptome-wide,
using augmented Ψ profiling methods to ensure possible disease-relevant substrates are identified (Aim 1).
With PUS10 target sites defined, I will systematically profile the effects of PUS10-dependent Ψ on tRNA
function and gene expression, using engineered cell lines with temporal control of PUS10 activity to
discriminate between the direct effects of tRNA and mRNA pseudouridylation (Aim 2). I will then relate these
molecular perturbations to IBD-relevant cellular physiology—identifying the precise aspects of EMT directly
regulated by PUS10’s pseudouridylation activity (Aim 3).
Completion of the proposed work will significantly advance our understanding of the poorly characterized IBD
risk gene PUS10. These studies will comprehensively determine the molecular consequences of PUS10-
dependent pseudouridylation and delineate its role in the regulation of EMT—a cellular process of significant
clinical relevance to IBD pathology.

## Key facts

- **NIH application ID:** 10387059
- **Project number:** 1F31DK129022-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Cole Lewis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,917
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387059

## Citation

> US National Institutes of Health, RePORTER application 10387059, Functional Characterization of the Pseudouridine Synthase PUS10 (1F31DK129022-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10387059. Licensed CC0.

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