Principles of mRNA control by human PUM proteins elucidated from multimodal experiments and integrative data analysis
Open accessPublished version of a preprint
Abstract
The human PUF-family proteins, PUM1 and PUM2, posttranscriptionally 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 versus nonfunctional 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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- 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
- Cold Spring Harbor Laboratory
- Published
- 2020-08-04
- Volume
- 26
- Issue
- 11
- Pages
- 1680-1703
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC7566576
- OpenAlex
- W3047584855
- Cited by
- 22
- References
- 9
- 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
- hybrid
- doi.org
- 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 Institute of General Medical Sciences, National Institutes of Health (R35 GM128637, R01 GM105707)
- National Institute of Neurological Disorders and Stroke, grant/award number (R01NS100788)
- NIH grant/award number (1UG3TR003149, UM1 HG009382, R01 CA213214 01)
- the National Science Foundation Graduate Research Fellowship (DGE1256260)
- NCI through the Rogel Cancer Center support grant (P30CA046592)
- 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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