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

Genome Res. 2019 Jul;29(7):1100-1114. Epub 2019 Jun 21
Charles E Vejnar 1 , Mario Abdel Messih 1 , Carter M Takacs 2 , Valeria Yartseva 3 , Panos Oikonomou 4 , Romain Christiano 5 , Marlon Stoeckius 6 , Stephanie Lau 1 , Miler T Lee 7 , Jean-Denis Beaudoin 1 , Damir Musaev 1 , Hiba Darwich-Codore 1 , Tobias C Walther 8 , Saeed Tavazoie 9 , Daniel Cifuentes 10 , Antonio J Giraldez 11
Charles E Vejnar 1 , Mario Abdel Messih 1 , Carter M Takacs 2 , Valeria Yartseva 3 , Panos Oikonomou 4 , Romain Christiano 5 , Marlon Stoeckius 6 , Stephanie Lau 1 , Miler T Lee 7 , Jean-Denis Beaudoin 1 , Damir Musaev 1 , Hiba Darwich-Codore 1 , Tobias C Walther 8 , Saeed Tavazoie 9 , Daniel Cifuentes 10 , Antonio J Giraldez 11
+ et al

[No authors listed]

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 Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
  • 9 Department of Biochemistry and Molecular Biophysics, and Department of Systems Biology, Columbia University, New York, New York 10032, USA.
  • 10 Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
  • 11 Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

摘要


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 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 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.