Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Division of Biology, Kansas State University, Manhattan, KS 66506, USA
Development. 2021 Feb 5;148(3):dev195230. doi: 10.1242/dev.195230.
The notochord is a defining feature of the chordates. The transcription factor Brachyury (Bra) is a key regulator of notochord fate but here we show that it is not a unitary master regulator in the model chordate Ectopic Bra expression only partially reprograms other cell types to a notochord-like transcriptional profile and a subset of notochord-enriched genes is unaffected by CRISPR Bra disruption. We identify Foxa.a and Mnx as potential co-regulators, and find that combinatorial cocktails are more effective at reprogramming other cell types than Bra alone. We reassess the network relationships between Bra, Foxa.a and other components of the notochord gene regulatory network, and find that Foxa.a expression in the notochord is regulated by vegetal FGF signaling. It is a direct activator of Bra expression and has a binding motif that is significantly enriched in the regulatory regions of notochord-enriched genes. These and other results indicate that Bra and Foxa.a act together in a regulatory network dominated by positive feed-forward interactions, with neither being a classically defined master regulator.
脊索是脊索动物的一个显著特征。转录因子 Brachyury（Bra）是脊索命运的关键调节因子，但在这里我们表明，它不是模型脊索动物中的单一主调节因子，异位 Bra 表达仅部分将其他细胞类型重新编程为类似于脊索的转录特征，并且一部分富含脊索的基因不受 CRISPR Bra 破坏的影响。我们确定 Foxa.a 和 Mnx 为潜在的共调节因子，并发现组合鸡尾酒比单独的 Bra 更有效地重新编程其他细胞类型。我们重新评估了 Bra、Foxa.a 和脊索基因调控网络的其他成分之间的网络关系，发现 Foxa.a 在脊索中的表达受植物 FGF 信号的调节。它是 Bra 表达的直接激活剂，并且具有在富含脊索的基因的调节区域中显著富集的结合基序。这些和其他结果表明，Bra 和 Foxa.a 在以正反馈相互作用为主导的调控网络中共同作用，两者都不是经典定义的主调节因子。
