Sood Amogh, Zhang Bin
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States.
Front Genet. 2021 Jan 22;11:636724. doi: 10.3389/fgene.2020.636724. eCollection 2020.
The Waddington landscape provides an intuitive metaphor to view development as a ball rolling down the hill, with distinct phenotypes as basins and differentiation pathways as valleys. Since, at a molecular level, cell differentiation arises from interactions among the genes, a mathematical definition for the Waddington landscape can, in principle, be obtained by studying the gene regulatory networks. For eukaryotes, gene regulation is inextricably and intimately linked to histone modifications. However, the impact of such modifications on both landscape topography and stability of attractor states is not fully understood. In this work, we introduced a minimal kinetic model for gene regulation that combines the impact of both histone modifications and transcription factors. We further developed an approximation scheme based on variational principles to solve the corresponding master equation in a second quantized framework. By analyzing the steady-state solutions at various parameter regimes, we found that histone modification kinetics can significantly alter the behavior of a genetic network, resulting in qualitative changes in gene expression profiles. The emerging epigenetic landscape captures the delicate interplay between transcription factors and histone modifications in driving cell-fate decisions.
沃丁顿景观提供了一个直观的比喻，将发育视为一个球滚下山坡，不同的表型作为盆地，分化途径作为山谷。由于在分子水平上，细胞分化源于基因之间的相互作用，原则上，通过研究基因调控网络可以获得沃丁顿景观的数学定义。对于真核生物，基因调控与组蛋白修饰有着千丝万缕的紧密联系。然而，这种修饰对景观地形和吸引子状态稳定性的影响尚未完全了解。在这项工作中，我们引入了一个最小基因调控动力学模型，该模型结合了组蛋白修饰和转录因子的影响。我们进一步基于变分原理开发了一种近似方案，以在二次量子化框架中求解相应的主方程。通过分析各种参数范围内的稳态解，我们发现组蛋白修饰动力学可以显著改变遗传网络的行为，导致基因表达谱的定性变化。新出现的表观遗传景观捕捉了转录因子和组蛋白修饰在驱动细胞命运决定中的微妙相互作用。
