Letter | Published:

Systematic discovery of structural elements governing stability of mammalian messenger RNAs

Nature volume 485, pages 264268 (10 May 2012) | Download Citation

Abstract

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 efforts1,2,3, 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 stability3, alternative splicing4 and localization3. 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 biology5. Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence3,6. Here we present a computational framework based on context-free grammars3,7 and mutual information2 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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Primary accessions

Gene Expression Omnibus

Data deposits

The microarray and high-throughput sequencing data are deposited at GEO under the umbrella accession number GSE35800.

References

  1. 1.

    et al. High-resolution gene expression profiling for simultaneous kinetic parameter analysis of RNA synthesis and decay. RNA 14, 1959–1972 (2008)

  2. 2.

    , & A universal framework for regulatory element discovery across all genomes and data types. Mol. Cell 28, 337–350 (2007)

  3. 3.

    , & Computational prediction of RNA structural motifs involved in posttranscriptional regulatory processes. Proc. Natl Acad. Sci. USA 105, 14885–14890 (2008)

  4. 4.

    et al. Deciphering the splicing code. Nature 465, 53–59 (2010)

  5. 5.

    , , , & Understanding the transcriptome through RNA structure. Nature Rev. Genet. 12, 641–655 (2011)

  6. 6.

    , , & RNAProfile: an algorithm for finding conserved secondary structure motifs in unaligned RNA sequences. Nucleic Acids Res. 32, 3258–3269 (2004)

  7. 7.

    The language of genes. Nature 420, 211–217 (2002)

  8. 8.

    , & Secondary structure prediction for aligned RNA sequences. J. Mol. Biol. 319, 1059–1066 (2002)

  9. 9.

    et al. Genome-wide measurement of RNA secondary structure in yeast. Nature 467, 103–107 (2010)

  10. 10.

    , & Revealing global regulatory perturbations across human cancers. Mol. Cell 36, 900–911 (2009)

  11. 11.

    et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011)

  12. 12.

    & Silencing or knocking out eukaryotic gene expression by oligodeoxynucleotide decoys. Crit. Rev. Eukaryot. Gene Expr. 16, 23–30 (2006)

  13. 13.

    & Isolation of specific RNA-binding proteins using the streptomycin-binding RNA aptamer. Nature Protocols 1, 637–640 (2006)

  14. 14.

    , , , & Two homologous genes, originated by duplication, encode the human hnRNP proteins A2 and A1. Nucleic Acids Res. 22, 1996–2002 (1994)

  15. 15.

    , & The cap-to-tail guide to mRNA turnover. Nature Rev. Mol. Cell Biol. 2, 237–246 (2001)

  16. 16.

    & Antagonistic role of hnRNP A1 and KSRP in the regulation of let-7a biogenesis. Nature Struct. Mol. Biol. 17, 1011–1018 (2010)

  17. 17.

    et al. Systematic variation in gene expression patterns in human cancer cell lines. Nature Genet. 24, 227–235 (2000)

  18. 18.

    & CLIP: crosslinking and immunoprecipitation of in vivo RNA targets of RNA-binding proteins. Methods Mol. Biol. 488, 85–98 (2008)

  19. 19.

    , & RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts. Nature Protocols 1, 302–307 (2006)

  20. 20.

    et al. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464–469 (2008)

  21. 21.

    & An integrated ChIP-seq analysis platform with customizable workflows. BMC Bioinformatics 12, 277–294 (2011)

  22. 22.

    & Predicting gene expression from sequence. Cell 117, 185–198 (2004)

  23. 23.

    et al. RNA secondary structure in mutually exclusive splicing. Nature Struct. Mol. Biol. 18, 159–168 (2011)

  24. 24.

    , , & Nuclear import of histone deacetylase 5 by requisite nuclear localization signal phosphorylation. Mol. Cell Proteomics 10, M110.004317 (2011)

  25. 25.

    , , & Universal sample preparation method for proteome analysis. Nature Methods 6, 359–362 (2009)

  26. 26.

    , , & Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460, 479–486 (2009)

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Acknowledgements

We thank the members of the Tavazoie laboratory for comments on the project and manuscript. We are also grateful to N. Pencheva, B. Tsui, S. Tavazoie and L. Dölken for their intellectual and technical contributions. L.F. was supported by a Ruth L. Kirschstein National Research Service Award (T32-GM066699). S.T. was supported by grants from NHGRI (2R01HG003219) and the NIH Director's Pioneer Award.

Author information

Author notes

    • Hani Goodarzi
    • , Hamed S. Najafabadi
    • , Panos Oikonomou
    •  & Saeed Tavazoie

    Present addresses: Department of Biochemistry and Molecular Biophysics, and Initiative in Systems Biology, Columbia University, New York, New York 10032, USA (H.G., P.O., S.T.); The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada (H.S.N.).

Affiliations

  1. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08540, USA

    • Hani Goodarzi
    • , Panos Oikonomou
    •  & Saeed Tavazoie
  2. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08540, USA

    • Hani Goodarzi
    • , Panos Oikonomou
    • , Todd M. Greco
    • , Ileana M. Cristea
    •  & Saeed Tavazoie
  3. Institute of Parasitology, McGill University, Montreal, Quebec H3G1Y6, Canada

    • Hamed S. Najafabadi
    •  & Reza Salavati
  4. McGill Centre for Bioinformatics, McGill University, Montreal, Quebec H3G1Y6, Canada

    • Hamed S. Najafabadi
    •  & Reza Salavati
  5. Laboratory of Systems Cancer Biology, Rockefeller University, New York, New York 10065, USA

    • Lisa Fish
  6. Department of Biochemistry, McGill University, Montreal, Quebec H3G1Y6, Canada

    • Reza Salavati

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Contributions

H.G., H.S.N. and S.T. conceived and designed the study. H.G. and H.S.N. developed TEISER. R.S. contributed to the execution of the study. H.G., H.S.N., T.M.G., P.O., I.M.C. and S.T. designed the experiments. H.G., P.O., L.F. and T.M.G. performed the experiments. H.G., H.S.N. and T.M.G. analysed the results. H.G., H.S.N. and S.T. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Saeed Tavazoie.

Supplementary information

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    Supplementary Information

    This file contains Supplementary Figures 1-15, Supplementary Tables 1-2 and additional references.

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DOI

https://doi.org/10.1038/nature11013

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