# Variant induced RNA structure change in human genetic disease

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $416,440

## Abstract

SUMMARY
My research program focuses on quantitatively characterizing the role of RNA structure in post-transcriptional
regulatory processes. Comparisons of protein and messenger RNA (mRNA) abundance at genome scale reveal
low correlation between the two gene expression levels in most human tissues and other organisms. This poor
correlation suggests that a significant amount of gene regulation occurs post-transcriptionally. To discover
elements in mRNAs that control their activities, we measure the effects of human disease-associated structure
variants that map to non-coding regions of the transcriptome. Specifically, we integrate computational structure
prediction with high-throughput allele-specific chemical structure probing in vivo to assess the functional
consequences of RNA structure change. We also establish the causality of these variants by using quantitative
reporter assays to measure translation efficiency, splicing, and mRNA stability. In total, these experiments
provide molecular explanations of disease mechanisms. To support these goals, we develop, implement, and
apply both computational and experimental approaches to study RNA structure in the cell. Our proposed
research program will further develop two important technological innovations. The first is a hybrid
experimental/computational approach for studying precursor and mature mRNA structure simultaneously in vivo;
this approach integrates mutational profiling of SHAPE-MaP data (Selective 2’-Hydroxyl Acylation by Primer
Extension – Mutational Profiling) with Boltzmann suboptimal sampling of the secondary structural ensemble. The
second innovation is SHAPE-JuMP, which uses a bifunctional RNA modification reagent and a highly processive
reverse transcriptase that “jumps” across chemical crosslinks to probe through-space three-dimensional contacts
in RNA. We will use these technologies to establish the structures of both precursor and mature mRNAs. In
addition, we will extend the biological scope of our work by using these technologies to collaboratively investigate
inter- and intramolecular interactions in positive strand RNA viruses. In sum, this program will identify novel RNA
structure motifs that regulate the functions of precursor and mature mRNAs and viral genomes.

## Key facts

- **NIH application ID:** 10868426
- **Project number:** 5R35GM140844-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Alain T Laederach
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $416,440
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868426

## Citation

> US National Institutes of Health, RePORTER application 10868426, Variant induced RNA structure change in human genetic disease (5R35GM140844-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10868426. Licensed CC0.

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