Rashid Mubasher, Hegade Abhiram
Department of Mathematics and Statistics, Indian Institute of Technology Kanpur, Kanpur, 208016, India.
Department of Mathematics, University of Florida, Gainesville, 32601, FL, USA.
NPJ Syst Biol Appl. 2025 Jan 2;11(1):2. doi: 10.1038/s41540-024-00483-w.
Interconnected feedback loops are prevalent across biological mechanisms, including cell fate transitions enabled by epigenetic mechanisms in carcinomas. However, the operating principles of these networks remain largely unexplored. Here, we identify numerous interconnected feedback loops implicated in cell lineage decisions, which we discover to be the hallmarks of lower- and higher-dimensional state space. We demonstrate that networks having higher centrality nodes have restricted state space while those with lower centrality nodes have higher dimensional state space. The topologically distinct networks with identical node or loop counts have different steady-state distributions, highlighting the crucial influence of network structure on emergent dynamics. Further, regardless of topology, networks with autoregulated nodes exhibit multiple steady states, thereby "liberating" network dynamics from absolute topological control. These findings unravel the design principles of multistable networks implicated in fate decisions and can have crucial implications in engineering or comprehending multi-fate decision circuits.
相互连接的反馈回路在各种生物机制中普遍存在，包括癌症中由表观遗传机制促成的细胞命运转变。然而，这些网络的运作原理在很大程度上仍未被探索。在这里，我们识别出许多与细胞谱系决定有关的相互连接的反馈回路，我们发现这些回路是低维和高维状态空间的标志。我们证明，具有较高中心性节点的网络具有受限的状态空间，而具有较低中心性节点的网络具有更高维度的状态空间。具有相同节点或回路数量的拓扑结构不同的网络具有不同的稳态分布，这突出了网络结构对涌现动力学的关键影响。此外，无论拓扑结构如何，具有自调节节点的网络都表现出多个稳态，从而将网络动力学从绝对的拓扑控制中“解放”出来。这些发现揭示了与命运决定有关的多稳态网络的设计原则，并且可能对工程设计或理解多命运决策电路具有至关重要的意义。
