mRNA 5’ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay

This publication — which has just appeared today — has little to do with gene-environment interactions, per se. Rather, it answers some very important questions that many of us have pondered, dating back 30-40 years (i.e., does the mRNA itself contain specific nucleotide sequences that in some cases regulate its degree of expression, rates of synthesis and/or degradation?). The answer to this question is a resounding YES: specific combinations (in the noncoding portion of the mRNA) can lead to as much as 200-fold differences in expression of the gene having this particular mRNA…!! 😊



mRNA regulatory sequences control gene expression at multiple levels — including translation

initiation, and mRNA decay. The 5’ terminal sequences of mRNAs have unique regulatory

potential because of their proximity to key post-transcriptional regulators. Here we have systematically

probed the function of 5’ terminal sequences in gene expression in human cells.

Using a library of reporter mRNAs initiating with all possible 7-mer sequences at their 5’

ends, we find an unexpected impact on transcription that underlies 200-fold differences in

mRNA expression. Library sequences that promote high levels of transcription mirrored

those found in native mRNAs and define two basic classes with similarities to classic Initiator

(Inr) and TCT core-promoter motifs. By comparing transcription, translation and decay

rates, we identify sequences that are optimized for both efficient transcription and growth-regulated

translation and stability — including variants of terminal oligopyrimidine (TOP)

motifs. We further show that 5’ sequences of endogenous mRNAs are enriched for multifunctional

TCT/TOP hybrid sequences. Together, our results reveal how 5’ sequences

define two general classes of mRNAs with distinct growth-responsive profiles of expression

across synthesis, translation, and decay.

Author summary

mRNAs are basic units of gene expression that are regulated throughout their life cycle,

including at steps of transcription, translation and decay. Key regulatory proteins for each

of these steps interact with the 5’ end of mRNAs. The adjacent 5’ sequence is therefore

uniquely positioned to encode regulatory motifs that influence their function. To profile

the function of terminal mRNA 5’ sequences, we developed a library of mRNAs with all

possible 7-nucleotide 5’ sequences. We identify unique motifs that are optimized for efficient

transcription, while other classes of sequences link mRNA translation and stability

to cellular growth signals. Overall, our results show how the terminal 5’ sequences of

mRNAs define distinct profiles of gene expression across the mRNA life cycle.

PLoS Genet Nov 2022; 18: e1010532

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