Duddu Atchuta Srinivas, Sahoo Sarthak, Hati Souvadra, Jhunjhunwala Siddharth, Jolly Mohit Kumar
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.
UG Programme, Indian Institute of Science, Bangalore, India.
J R Soc Interface. 2020 Sep;17(170):20200631. doi: 10.1098/rsif.2020.0631. Epub 2020 Sep 30.
Identifying the design principles of complex regulatory networks driving cellular decision-making remains essential to decode embryonic development as well as enhance cellular reprogramming. A well-studied network motif involved in cellular decision-making is a toggle switch-a set of two opposing transcription factors A and B, each of which is a master regulator of a specific cell fate and can inhibit the activity of the other. A toggle switch can lead to two possible states-(high A, low B) and (low A, high B)-and drives the 'either-or' choice between these two cell fates for a common progenitor cell. However, the principles of coupled toggle switches remain unclear. Here, we investigate the dynamics of three master regulators A, B and C inhibiting each other, thus forming three-coupled toggle switches to form a toggle triad. Our simulations show that this toggle triad can lead to co-existence of cells into three differentiated 'single positive' phenotypes-(high A, low B, low C), (low A, high B, low C) and (low A, low B, high C). Moreover, the hybrid or 'double positive' phenotypes-(high A, high B, low C), (low A, high B, high C) and (high A, low B, high C)-can coexist together with 'single positive' phenotypes. Including self-activation loops on A, B and C can increase the frequency of 'double positive' states. Finally, we apply our results to understand cellular decision-making in terms of differentiation of naive CD4 T cells into Th1, Th2 and Th17 states, where hybrid Th1/Th2 and hybrid Th1/Th17 cells have been reported in addition to the Th1, Th2 and Th17 ones. Our results offer novel insights into the design principles of a multi-stable network topology and provide a framework for synthetic biology to design tristable systems.
确定驱动细胞决策的复杂调控网络的设计原则，对于解码胚胎发育以及增强细胞重编程仍然至关重要。一个在细胞决策中得到充分研究的网络基序是双稳开关——一组两个相互对立的转录因子A和B，其中每个转录因子都是特定细胞命运的主要调节因子，并且可以抑制另一个的活性。双稳开关可以导致两种可能的状态——（高A，低B）和（低A，高B）——并驱动共同祖细胞在这两种细胞命运之间进行“非此即彼”的选择。然而，耦合双稳开关的原理仍不清楚。在这里，我们研究了三个主要调节因子A、B和C相互抑制的动力学，从而形成三个耦合的双稳开关以形成一个双稳三联体。我们的模拟表明，这个双稳三联体可以导致细胞共存于三种分化的“单阳性”表型——（高A，低B，低C）、（低A，高B，低C）和（低A，低B，高C）。此外，混合或“双阳性”表型——（高A，高B，低C）、（低A，高B，高C）和（高A，低B，高C）——可以与“单阳性”表型共存。在A、B和C上包含自激活环可以增加“双阳性”状态的频率。最后，我们应用我们的结果来理解原始CD4 T细胞分化为Th1、Th2和Th17状态过程中的细胞决策，其中除了Th1、Th2和Th17细胞外，还报道了混合的Th1/Th2和混合的Th1/Th17细胞。我们的结果为多稳态网络拓扑的设计原则提供了新的见解，并为合成生物学设计三稳态系统提供了一个框架。
