Article | Published:

RNA regulons in Hox 5′ UTRs confer ribosome specificity to gene regulation

Nature volume 517, pages 3338 (01 January 2015) | Download Citation

Abstract

Emerging evidence suggests that the ribosome has a regulatory function in directing how the genome is translated in time and space. However, how this regulation is encoded in the messenger RNA sequence remains largely unknown. Here we uncover unique RNA regulons embedded in homeobox (Hox) 5′ untranslated regions (UTRs) that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral internal ribosome entry sites (IRESs), are found in subsets of Hox mRNAs. They facilitate ribosome recruitment and require the ribosomal protein RPL38 for their activity. Despite numerous layers of Hox gene regulation, these IRES elements are essential for converting Hox transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by an additional regulatory element that we term the translation inhibitory element (TIE), which blocks cap-dependent translation of transcripts. Together, these data uncover a new paradigm for ribosome-mediated control of gene expression and organismal development.

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Accessions

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Hoxa4 5′ UTR sequence has been deposited in GenBank under accession number KM596709. All chemical mapping datasets have been deposited at the RNA Mapping Database (http://rmdb.stanford.edu) under the following accession codes: (1) Full-length: HOXA5_STD_0000, HOXA9_STD_0000; (2) Hoxa9 TIE: HOXA9A_STD_0001; (3) Hoxa9 IRES: HOXA9D_STD_0001, HOXA9D_STD_0002, HOXA9D_1M7_0001, and HOXA9D_RSQ_0001.

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Acknowledgements

We would like to thank members of the Barna laboratory and D. Ruggero for discussion and critical reading of the manuscript. We thank E. Sarinay Cenik for advice with RNA pull-down experiments; and Y. Rim, A. Sapiro and A. Mateo for technical assistance. This work was supported by the Agency of Science, Technology and Research of Singapore (S.X.), Stanford Graduate Fellowship (S.T.), Human Frontier Science Program Fellowship (K.F.), NIH R01 GM102519 (R.D.), NIH Director’s New Innovator Award, 7DP2OD00850902 (M.B.), Alfred P. Sloan Research Fellowship (M.B.) and Pew Scholars Award (M.B.).

Author information

Affiliations

  1. Department of Developmental Biology, Stanford University, Stanford, California 94305, USA

    • Shifeng Xue
    • , Kotaro Fujii
    •  & Maria Barna
  2. Department of Genetics, Stanford University, Stanford, California 94305, USA

    • Shifeng Xue
    • , Kotaro Fujii
    •  & Maria Barna
  3. Tetrad Graduate Program, University of California, San Francisco, San Francisco, California 94158, USA

    • Shifeng Xue
  4. Department of Biochemistry, Stanford University, Stanford, California 94305, USA

    • Siqi Tian
    • , Wipapat Kladwang
    •  & Rhiju Das
  5. Department of Physics, Stanford University, Stanford, California 94305, USA

    • Rhiju Das

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Contributions

M.B. conceived and supervised the project; S.X. and M.B. designed experiments; S.X. performed all experiments with help from K.F. for 5′ RACE and sucrose gradient fractionation; S.T. and R.D. designed the RNA structure experiments; S.T. and W.K. performed the RNA structure experiments and analysed results; S.X. and M.B. wrote the manuscript with contributions from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Maria Barna.

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Supplementary information

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  1. 1.

    Supplementary Table 1

    This file contains primer sequences.

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DOI

https://doi.org/10.1038/nature14010

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