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Genome Res. 2019 Jul;29(7):1100-1114. doi: 10.1101/gr.245159.118. Epub 2019 Jun 21.

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

Author information

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

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.

PMID:
31227602
DOI:
10.1101/gr.245159.118

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