Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, 69120 Heidelberg, Germany.
Heidelberg University, Centre for Organismal Studies (COS) Heidelberg, 69120 Heidelberg, Germany.
Cell Rep. 2021 Jan 5;34(1):108577. doi: 10.1016/j.celrep.2020.108577.
Early lineage-specific master regulators are essential for the specification of cell types. However, once cells are committed to a specific fate, it is critical to restrict the activity of such factors to enable differentiation. To date, it remains unclear how these factors are silenced. Using the Drosophila mesoderm as a model and a comparative genomic approach, we identify the Hox transcription factor Ultrabithorax (Ubx) to be critical for the repression of the master regulator Twist. Mesoderm-specific Ubx loss-of-function experiments using CRISPR-Cas9 and overexpression studies demonstrate that Ubx majorly impacts twist transcription. A mechanistic analysis reveals that Ubx requires the NK-homeodomain protein Tinman to bind to the twist promoter. Furthermore, we find these factor interactions to be critical for silencing by recruiting the Polycomb DNA binding protein Pleiohomeotic. Altogether, our data reveal that Ubx is a critical player in mediating the silencing of Twist, which is crucial for coordinated muscle differentiation.
早期的谱系特异性主调控因子对于细胞类型的特化是必不可少的。然而，一旦细胞被特化为特定的命运，限制这些因子的活性以促进分化就变得至关重要。迄今为止，这些因子是如何沉默的仍然不清楚。我们使用果蝇中胚层作为模型，并采用比较基因组学方法，确定了 Hox 转录因子 Ultrabithorax (Ubx) 对于主调控因子 Twist 的抑制是至关重要的。使用 CRISPR-Cas9 的中胚层特异性 Ubx 功能丧失实验和过表达研究表明，Ubx 主要影响 twist 转录。机制分析表明，Ubx 需要 NK 同源域蛋白 Tinman 来结合 twist 启动子。此外，我们发现这些因子相互作用对于沉默至关重要，因为它可以招募 Polycomb DNA 结合蛋白 Pleiohomeotic。总之，我们的数据表明，Ubx 是介导 Twist 沉默的关键因子，这对于协调肌肉分化是至关重要的。
