IIT Bombay, Department of Physics, Mumbai, 400076, India.
Indian Institute of Science, Centre for High Energy Physics, Bangalore, 560012, India.
Sci Rep. 2018 May 9;8(1):7358. doi: 10.1038/s41598-018-25556-9.
Waddington's epigenetic landscape provides a phenomenological understanding of the cell differentiation pathways from the pluripotent to mature lineage-committed cell lines. In light of recent successes in the reverse programming process there has been significant interest in quantifying the underlying landscape picture through the mathematics of gene regulatory networks. We investigate the role of time delays arising from multi-step chemical reactions and epigenetic rearrangement on the cell differentiation landscape for a realistic two-gene regulatory network, consisting of self-promoting and mutually inhibiting genes. Our work provides the first theoretical basis of the transdifferentiation process in the presence of delays, where one differentiated cell type can transition to another directly without passing through the undifferentiated state. Additionally, the interplay of time-delayed feedback and a time dependent chemical drive leads to long-lived oscillatory states in appropriate parameter regimes. This work emphasizes the important role played by time-delayed feedback loops in gene regulatory circuits and provides a framework for the characterization of epigenetic landscapes.
Waddington 的表观遗传景观为多能性到成熟谱系定向细胞系的细胞分化途径提供了一种现象学理解。鉴于最近在反向编程过程中的成功，人们对通过基因调控网络的数学来量化潜在的景观图景产生了浓厚的兴趣。我们研究了多步化学反应和表观遗传重排引起的时间延迟在细胞分化景观中的作用，该景观适用于由自我促进和相互抑制基因组成的现实的双基因调控网络。我们的工作为存在延迟时的转分化过程提供了第一个理论基础，其中一种分化的细胞类型可以直接转变为另一种细胞类型，而无需经过未分化状态。此外，时滞反馈和随时间变化的化学驱动力的相互作用导致在适当的参数范围内产生长寿命的振荡状态。这项工作强调了时滞反馈环在基因调控电路中所起的重要作用，并为描述表观遗传景观提供了一个框架。
