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PreprintCited by 22RNA Research and SplicingRNA and protein synthesis mechanismsRNA regulation and disease

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Principles of mRNA control by human PUM proteins elucidated from multi-modal experiments and integrative data analysis

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Wolfe, Michael B., Schagat, Trista L., Paulsen, Michelle T., Magnuson, Brian, Ljungman, Mats, Park, Daeyoon, Zhang, Chi, Campbell, Zachary T., Goldstrohm, Aaron C., Freddolino, Peter L.·2020·RNA
DOI 10.1101/2020.04.01.019836PMC PMC7566576

Preprint — published as 10.1261/rna.077362.120 · Paper page

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Abstract

The human PUF-family proteins, PUM1 and PUM2, post-transcriptionally regulate gene expression by binding to a PUM recognition element (PRE) in the 3’ UTR of target mRNAs. Hundreds of PUM1/2 targets have been identified from changes in steady state RNA levels; however, prior studies could not differentiate between the contributions of changes in transcription and RNA decay rates. We applied metabolic labeling to measure changes in RNA turnover in response to depletion of PUM1/2, showing that human PUM proteins regulate expression almost exclusively by changing RNA stability. We also applied an in vitro selection workflow to precisely identify the binding preferences of PUM1 and PUM2. By integrating our results with prior knowledge, we developed a ‘rulebook’ of key contextual features that differentiate functional vs. non-functional PREs, allowing us to train machine learning models that accurately predict the functional regulation of RNA targets by the human PUM proteins.

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Metadata

Authors
Wolfe, M. B., Schagat, T. L., Paulsen, M. T., Magnuson, B., Ljungman, M., Park, D., Zhang, C., Campbell, Z. T., Goldstrohm, A. C., & Freddolino, P. L.
Affiliations
  • University of Michigan (US)
  • Promega (United States) (US)
  • University of Minnesota (US)
  • The University of Texas at Dallas (US)
Corresponding author
Freddolino, Peter L.
ORCID
Venue
RNA
Publisher
openRxiv
Published
2020-04-01
Volume
26
Issue
11
Pages
1680-1703
ISSN
1355-8382 (ISSN-L)
DOI
10.1101/2020.04.01.019836
PMC
PMC7566576
OpenAlex
W3047584855
Cited by
22
References
1
Citations by year
2026: 3 · 2025: 1 · 2024: 8 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 1
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • RNA (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Science Foundation (1256260)
  • National Institutes of Health (UG3TR003149)
  • Rogel Cancer Center, University of Michigan (P30 CA046592)
  • National Human Genome Research Institute (UM1HG009382)
  • National Cancer Institute (R01CA213214, P30CA046592)
  • National Institute of General Medical Sciences (GM128637, R01GM105707, R35GM128637)
  • National Institute of Neurological Disorders and Stroke (R01NS100788, R01NS114018)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
PUM1, PUM2, PUF proteins, post-transcriptional regulation, mRNA stability, RNA turnover, 3' untranslated region, in vitro selection, metabolic labeling
MeSH terms
Machine Learning, Whole Genome Sequencing, Gene Expression Regulation, Humans, RNA Processing, Post-Transcriptional, RNA, Messenger, RNA-Binding Proteins, 3' Untranslated Regions, RNA Stability, HEK293 Cells

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