假尿苷
信使核糖核酸
翻译(生物学)
核糖体
核糖核酸
计算生物学
理论(学习稳定性)
转移RNA
计算机科学
化学
细胞生物学
生物
生物化学
基因
机器学习
作者
Kathrin Leppek,Gun Woo Byeon,Wipapat Kladwang,Hannah K. Wayment-Steele,Craig H. Kerr,Adele F. Xu,Do Soon Kim,Ved V. Topkar,Christian A. Choe,Daphna Rothschild,Gerald C. Tiu,Roger Wellington-Oguri,Kotaro Fujii,Eesha Sharma,Andrew Watkins,John J. Nicol,Jonathan Romano,Bojan Tunguz,Eterna Participants,Maria Barna,Rhiju Das
标识
DOI:10.1101/2021.03.29.437587
摘要
SUMMARY Therapeutic mRNAs and vaccines are being developed for a broad range of human diseases, including COVID-19. However, their optimization is hindered by mRNA instability and inefficient protein expression. Here, we describe design principles that overcome these barriers. We develop a new RNA sequencing-based platform called PERSIST-seq to systematically delineate in-cell mRNA stability, ribosome load, as well as in-solution stability of a library of diverse mRNAs. We find that, surprisingly, in-cell stability is a greater driver of protein output than high ribosome load. We further introduce a method called In-line-seq, applied to thousands of diverse RNAs, that reveals sequence and structure-based rules for mitigating hydrolytic degradation. Our findings show that “superfolder” mRNAs can be designed to improve both stability and expression that are further enhanced through pseudouridine nucleoside modification. Together, our study demonstrates simultaneous improvement of mRNA stability and protein expression and provides a computational-experimental platform for the enhancement of mRNA medicines.
科研通智能强力驱动
Strongly Powered by AbleSci AI