Developmentally Programmed Tankyrase Activity Upregulates β-Catenin and Licenses Progression of Embryonic Genome Activation

• Published in: Developmental cell 2020-06, Vol.53 (5), p.545-560.e7
• Main Authors: Gambini, Andrés, Stein, Paula, Savy, Virginia, Grow, Edward J., Papas, Brian N., Zhang, Yingpei, Kenan, Anna C., Padilla-Banks, Elizabeth, Cairns, Bradley R., Williams, Carmen J.
• Format: Article
• Language: English
• Subjects: Animals; ATAC-seq; axin; beta Catenin - genetics; beta Catenin - metabolism; Blastocyst - cytology; Blastocyst - metabolism; embryonic genome activation; Gene Expression Regulation, Developmental; Histones - metabolism; Mice; Mice, Inbred C57BL; mouse; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Oocytes - cytology; Oocytes - metabolism; post-transcriptional regulation; preimplantation embryo; Proto-Oncogene Proteins c-myc - metabolism; RNA, Ribosomal - genetics; RNA, Ribosomal - metabolism; tankyrase; Tankyrases - genetics; Tankyrases - metabolism; Up-Regulation; WNT signaling pathway; β-catenin
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.04.018

Embryonic genome activation (EGA) is orchestrated by an intrinsic developmental program initiated during oocyte maturation with translation of stored maternal mRNAs. Here, we show that tankyrase, a poly(ADP-ribosyl) polymerase that regulates β-catenin levels, undergoes programmed translation during oocyte maturation and serves an essential role in mouse EGA. Newly translated TNKS triggers proteasomal degradation of axin, reducing targeted destruction of β-catenin and promoting β-catenin-mediated transcription of target genes, including Myc. MYC mediates ribosomal RNA transcription in 2-cell embryos, supporting global protein synthesis. Suppression of tankyrase activity using knockdown or chemical inhibition causes loss of nuclear β-catenin and global reductions in transcription and histone H3 acetylation. Chromatin and transcriptional profiling indicate that development arrests prior to the mid-2-cell stage, mediated in part by reductions in β-catenin and MYC. These findings indicate that post-transcriptional regulation of tankyrase serves as a ligand-independent developmental mechanism for post-translational β-catenin activation and is required to complete EGA. [Display omitted] •Tankyrase protein levels increase during mouse oocyte maturation•Tankyrase promotes β-catenin activity in a ligand-independent fashion•β-catenin activates MYC-mediated ribosomal biogenesis•Tankyrase activity is essential for embryonic genome activation during the 2C stage β-catenin signaling during development is normally mediated by Wnt ligands. Gambini et al. show that ligand-independent, post-transcriptional regulation of tankyrase levels during mouse oocyte maturation leads to β-catenin activity necessary for embryonic genome activation.