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Systematic discovery of structural elements governing stability of mammalian messenger RNAs
Open accessAbstract
Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts, the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including--but not limited to--transcript stability, alternative splicing and localization. There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence. Here we present a computational framework based on context-free grammars and mutual information that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour.
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“Nonetheless, the stabilizing/destabilizing roles predicted from this analysis were, on average, closely correlated with genome-wide measurements of RNA stability obtained previously from a thio-U pulse–chase experiment22”
From A compendium of RNA-binding motifs for decoding gene regulation (2013) · cites this paper as [22]
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“very different motifs have been previously described for different HNRNPA family members from human and Drosophila19–22, whereas the RNAcompete motifs for the same proteins are closely related”
From A compendium of RNA-binding motifs for decoding gene regulation (2013) · cites this paper as [22]
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Metadata
- Authors
- Goodarzi, H., Najafabadi, H. S., Oikonomou, P., Greco, T. M., Fish, L., Salavati, R., Cristea, I. M., & Tavazoie, S.
- Affiliations
- Princeton University (US)
- McGill University (CA)
- Rockefeller University (US)
- Corresponding author
- Tavazoie, Saeed
- ORCID
- Venue
- Nature
- Published
- 2012-04-08
- Volume
- 485
- Issue
- 7397
- Pages
- 264-268
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3350620
- OpenAlex
- W2030581432
- Cited by
- 187
- References
- 26
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 6 · 2023: 7 · 2022: 12 · 2021: 9 · 2020: 23 · 2019: 8 · 2018: 9 · 2017: 13 · 2016: 13 · 2015: 17 · 2014: 17 · 2013: 25 · 2012: 11
- FWCI
- 8.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (DP1OD003787)
- National Institute on Drug Abuse (DP1DA026192)
- National Human Genome Research Institute (R01HG003219)
- National Institute of General Medical Sciences (T32GM066699)
- National Institute of Environmental Health Sciences (DP1ES022578)
- 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
- mRNA secondary structure, RNA stability, post-transcriptional regulation, RNA-binding proteins, HNRNPA2B1, cis-regulatory elements, context-free grammars, mutual information, alternative splicing, transcript localization, structural motifs
- MeSH terms
- Algorithms, Animals, Breast Neoplasms, Humans, Nucleic Acid Conformation, RNA, Messenger, Time Factors, Transcription, Genetic, Genome, Human, Gene Expression Regulation, Neoplastic, 3' Untranslated Regions, Gene Expression Profiling, RNA Stability, Genomics, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, RNA, Small Interfering, Cell Line, Tumor, Mice, Gene Knockdown Techniques, Nucleotide Motifs
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