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mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay
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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9731452/ https://www.ncbi.nlm.nih.gov/pubmed/36441824 http://dx.doi.org/10.1371/journal.pgen.1010532 |
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author | van den Elzen, Antonia M. G. Watson, Maegan J. Thoreen, Carson C. |
author_facet | van den Elzen, Antonia M. G. Watson, Maegan J. Thoreen, Carson C. |
author_sort | van den Elzen, Antonia M. G. |
collection | PubMed |
description | 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 multi-functional 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. |
format | Online Article Text |
id | pubmed-9731452 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-97314522022-12-09 mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay van den Elzen, Antonia M. G. Watson, Maegan J. Thoreen, Carson C. PLoS Genet Research Article 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 multi-functional 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. Public Library of Science 2022-11-28 /pmc/articles/PMC9731452/ /pubmed/36441824 http://dx.doi.org/10.1371/journal.pgen.1010532 Text en © 2022 van den Elzen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article van den Elzen, Antonia M. G. Watson, Maegan J. Thoreen, Carson C. mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay |
title | mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay |
title_full | mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay |
title_fullStr | mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay |
title_full_unstemmed | mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay |
title_short | mRNA 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay |
title_sort | mrna 5′ terminal sequences drive 200-fold differences in expression through effects on synthesis, translation and decay |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9731452/ https://www.ncbi.nlm.nih.gov/pubmed/36441824 http://dx.doi.org/10.1371/journal.pgen.1010532 |
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