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Genome wide analysis of 3′ UTR sequence elements and proteins regulating mRNA stability during maternal-to-zygotic transition in zebrafish

  1. Antonio J. Giraldez1,13,14
  1. 1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
  2. 2University of New Haven, West Haven, Connecticut 06516, USA;
  3. 3Department of Neuroscience, Genentech, Incorporated, South San Francisco, California 94080, USA;
  4. 4Department of Systems Biology, Columbia University, New York, New York 10032, USA;
  5. 5Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA;
  6. 6New York Genome Center, New York, New York 10013, USA;
  7. 7Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA;
  8. 8Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
  9. 9Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02124, USA;
  10. 10Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
  11. 11Department of Biochemistry and Molecular Biophysics, and Department of Systems Biology, Columbia University, New York, New York 10032, USA;
  12. 12Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA;
  13. 13Yale Stem Cell Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
  14. 14Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA

  1. ↵15 These authors contributed equally to this work.

  • Corresponding authors: dcb{at}bu.edu, antonio.giraldez{at}yale.edu

    • Abstract

    Posttranscriptional regulation plays a crucial role in shaping gene expression. During the maternal-to-zygotic transition (MZT), thousands of maternal transcripts are regulated. However, how different cis-elements and trans-factors are integrated to determine mRNA stability remains poorly understood. Here, we show that most transcripts are under combinatorial regulation by multiple decay pathways during zebrafish MZT. By using a massively parallel reporter assay, we identified cis-regulatory sequences in the 3′ UTR, including U-rich motifs that are associated with increased mRNA stability. In contrast, miR-430 target sequences, UAUUUAUU AU-rich elements (ARE), CCUC, and CUGC elements emerged as destabilizing motifs, with miR-430 and AREs causing mRNA deadenylation upon genome activation. We identified trans-factors by profiling RNA–protein interactions and found that poly(U)-binding proteins are preferentially associated with 3′ UTR sequences and stabilizing motifs. We show that this activity is antagonized by C-rich motifs and correlated with protein binding. Finally, we integrated these regulatory motifs into a machine learning model that predicts reporter mRNA stability in vivo.

    Footnotes

    • Received October 16, 2018.
    • Accepted June 7, 2019.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.