Multiplexed Assays of Human Disease-relevant Mutations Reveal UTR Dinucleotide Composition as a Major Determinant of RNA Stability

Dr. Lin, Chien-Ling - February, 2025

Revealing Sequence Determinants of RNA Degradation from Human Disease-relevant Mutations

RNA stability is a critical regulator of gene expression, yet its precise control mechanisms remain unclear. Fine-tuning RNA stability is essential for the proper expression of both endogenous and exogenous RNAs in human cells. Dr. Chien-Ling Lin’s group at the Institute of Molecular Biology used massively parallel reporter assays to systematically dissect the regulatory rules of RNA degradation by examining 12,000 human UTR sequences. Statistical modeling by Dr. Yen-Tsung Huang’s team at the Institute of Statistical Sciences revealed that exposure of UA dinucleotides and AU-rich sequences drives RNA degradation. Consistently, fast-turnover genes—such as those involved in innate immune response and appetite control—exhibit high UA dinucleotide ratios in their UTRs, and mutations that increase UA content reduce RNA half-life. This simple rule may serve as a screening tool for UTR mutation-mediated pathologies and guide the design of synthetic RNAs for therapeutic applications.