mRNA structure regulates protein expression through changes in functional half-life

Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous s...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 48; pp. 24075 - 24083
Main Authors:	Mauger, David M., Cabral, B. Joseph, Presnyak, Vladimir, Su, Stephen V., Reid, David W., Goodman, Brooke, Link, Kristian, Khatwani, Nikhil, Reynders, John, Moore, Melissa J., McFadyen, Iain J.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 26-11-2019
Series:	PNAS Plus
Subjects:	Amino acid sequence Biological Sciences Design modifications Gene expression Half-Life HeLa Cells Humans Information processing mRNA stability Nucleic Acid Conformation Nucleotide sequence Nucleotides PNAS Plus Protein Biosynthesis - physiology Protein expression Protein structure Proteins Proteins - metabolism RNA Stability RNA, Messenger - chemistry Secondary structure translation SHAPE modified nucleotides RNA structure mRNA therapuetics
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Summary:	Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous sequences. Here, we used 2 approaches, global inclusion of modified nucleotides and rational sequence design of exogenously delivered constructs, to understand the role of mRNA secondary structure independent from codon usage. Unexpectedly, highly expressed mRNAs contained a highly structured coding sequence (CDS). Modified nucleotides that stabilize mRNA secondary structure enabled high expression across a wide variety of primary sequences. Using a set of eGFP mRNAs with independently altered codon usage and CDS structure, we find that the structure of the CDS regulates protein expression through changes in functional mRNA half-life (i.e., mRNA being actively translated). This work highlights an underappreciated role of mRNA secondary structure in the regulation of mRNA stability.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: D.M.M., B.J.C., V.P., K.L., J.R., M.J.M., and I.J.M. designed research; D.M.M., B.J.C., V.P., S.V.S., D.W.R., B.G., and N.K. performed research; V.P., S.V.S., B.G., K.L., and N.K. contributed new reagents/analytic tools; D.M.M., B.J.C., V.P., S.V.S., D.W.R., B.G., and N.K. analyzed data; and D.M.M., B.J.C., V.P., M.J.M., and I.J.M. wrote the paper. 3Present address: Microbiology and Immunology Department, Dartmouth College, Hanover, NH 03756. Edited by Joseph D. Puglisi, Stanford University School of Medicine, Stanford, CA, and approved October 8, 2019 (received for review May 9, 2019) 2Present address: Department of Cell and Molecular Biology, Korro Bio, Cambridge, MA 02139. 4Present address: Data Sciences, Genomics, and Bioinformatics Department, Alexion Pharmaceuticals, Boston, MA 02210. 6Present address: Computational Sciences Department, LifeMine Therapeutics, Cambridge, MA 02140. 1Present address: Venture Labs, Flagship Pioneering, Cambridge, MA 02142.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1908052116