Nelson Andrew C, Cutty Stephen J, Gasiunas Saule N, Deplae Isabella, Stemple Derek L, Wardle Fiona C
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK; School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, UK.
Cell Rep. 2017 Jun 27;19(13):2782-2795. doi: 10.1016/j.celrep.2017.06.011.
T-box transcription factors T/Brachyury homolog A (Ta) and Tbx16 are essential for correct mesoderm development in zebrafish. The downstream transcriptional networks guiding their functional activities are poorly understood. Additionally, important contributions elsewhere are likely masked due to redundancy. Here, we exploit functional genomic strategies to identify Ta and Tbx16 targets in early embryogenesis. Surprisingly, we discovered they not only activate mesodermal gene expression but also redundantly regulate key endodermal determinants, leading to substantial loss of endoderm in double mutants. To further explore the gene regulatory networks (GRNs) governing endoderm formation, we identified targets of Ta/Tbx16-regulated homeodomain transcription factor Mixl1, which is absolutely required in zebrafish for endoderm formation. Interestingly, we find many endodermal determinants coordinately regulated through common genomic occupancy by Mixl1, Eomesa, Smad2, Nanog, Mxtx2, and Pou5f3. Collectively, these findings augment the endoderm GRN and reveal a panel of target genes underlying the Ta, Tbx16, and Mixl1 mutant phenotypes.
T 盒转录因子 T/Brachyury 同源物 A（Ta）和 Tbx16 对斑马鱼中胚层的正常发育至关重要。指导它们功能活动的下游转录网络目前了解甚少。此外，由于功能冗余，它们在其他方面的重要作用可能被掩盖。在此，我们利用功能基因组学策略来鉴定早期胚胎发育过程中 Ta 和 Tbx16 的靶标。令人惊讶的是，我们发现它们不仅激活中胚层基因表达，还冗余调控关键的内胚层决定因子，导致双突变体中内胚层大量缺失。为了进一步探索控制内胚层形成的基因调控网络（GRN），我们鉴定了 Ta/Tbx16 调控的同源域转录因子 Mixl1 的靶标，Mixl1 是斑马鱼内胚层形成绝对必需的因子。有趣的是，我们发现许多内胚层决定因子通过 Mixl1、Eomesa、Smad2、Nanog、Mxtx2 和 Pou5f3 共同占据基因组而受到协同调控。总的来说，这些发现扩展了内胚层 GRN，并揭示了一组导致 Ta、Tbx16 和 Mixl1 突变体表型的靶基因。
