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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The stabilizing/destabilizing roles predicted from the analysis were on average closely correlated with genome-wide measurements of RNA stability from a thio-U pulse-chase experiment.
“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]
Very different motifs have been previously described for different HNRNPA family members from human and Drosophila, whereas RNAcompete motifs for the same proteins are closely related.
“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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- 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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