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

    • 1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
    • 2University of New Haven, West Haven, Connecticut 06516, USA;
    • 3Department of Neuroscience, Genentech, Incorporated, South San Francisco, California 94080, USA;
    • 4Department of Systems Biology, Columbia University, New York, New York 10032, USA;
    • 5Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA;
    • 6New York Genome Center, New York, New York 10013, USA;
    • 7Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA;
    • 8Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
    • 9Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02124, USA;
    • 10Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA;
    • 11Department of Biochemistry and Molecular Biophysics, and Department of Systems Biology, Columbia University, New York, New York 10032, USA;
    • 12Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA;
    • 13Yale Stem Cell Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA;
    • 14Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA
    • 15 These authors contributed equally to this work.
Published June 21, 2019. Vol 29 Issue 7, pp. 1100-1114. https://doi.org/10.1101/gr.245159.118
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cover of Genome Research Vol 36 Issue 5
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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.

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