Department of Bioengineering, Indian Institute of Science, Bangalore, 560012, India.
Department of Mathematical Sciences, Montana State University, Bozeman, MT, 59717, USA.
NPJ Syst Biol Appl. 2024 Oct 24;10(1):123. doi: 10.1038/s41540-024-00433-6.
Elucidating the emergent dynamics of cellular differentiation networks is crucial to understanding cell-fate decisions. Toggle switch - a network of mutually repressive lineage-specific transcription factors A and B - enables two phenotypes from a common progenitor: (high A, low B) and (low A, high B). However, the dynamics of networks enabling differentiation of more than two phenotypes from a progenitor cell has not been well-studied. Here, we investigate the dynamics of a four-node network A, B, C, and D inhibiting each other, forming a toggle tetrahedron. Our simulations show that this network is multistable and predominantly allows for the co-existence of six hybrid phenotypes where two of the nodes are expressed relatively high as compared to the remaining two, for instance (high A, high B, low C, low D). Finally, we apply our results to understand naïve CD4 T cell differentiation into Th1, Th2, Th17 and Treg subsets, suggesting Th1/Th2/Th17/Treg decision-making to be a two-step process.
阐明细胞分化网络的涌现动力学对于理解细胞命运决定至关重要。拨动开关 - 一种相互抑制的谱系特异性转录因子 A 和 B 的网络 - 使来自共同祖细胞的两种表型成为可能：（高 A，低 B）和（低 A，高 B）。然而，从祖细胞分化出超过两种表型的网络的动力学尚未得到很好的研究。在这里，我们研究了一个由 A、B、C 和 D 四个节点相互抑制形成的拨动四面体的网络动力学。我们的模拟表明，该网络是多稳定的，主要允许六种混合表型共存，其中两个节点的表达相对较高，而其余两个节点的表达相对较低，例如（高 A、高 B、低 C、低 D）。最后，我们应用我们的结果来理解幼稚 CD4 T 细胞分化为 Th1、Th2、Th17 和 Treg 亚群，表明 Th1/Th2/Th17/Treg 的决策是一个两步过程。
