Effects of Collective Histone State Dynamics on Epigenetic Landscape and Kinetics of Cell Reprogramming.
Effects of Collective Histone State Dynamics on Epigenetic Landscape and Kinetics of Cell Reprogramming.
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DOI：
10.1038/srep16746
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发表时间：
2015-11-19
影响因子：
4.6
通讯作者：
Sasai M
中科院分区：
文献类型：
--
作者：
Ashwin SS;Sasai M
细胞重编程是通过瞬时中间状态从分化细胞状态转变为多能细胞状态的过程。在表观生成景观框架内，这一过程被视为景观上盆地之间的一系列转变；因此，表现出实验一致动态的模型景观的理论构建可以为理解重编程的表观遗传机制提供线索。我们提出了一个最小的基因网络模型，其中每个基因都受到转录因子结合/解除结合和组蛋白集体化学修饰的整合机制的调节。我们表明，每个基因位点周围许多组蛋白的缓慢集体变化改变了景观的拓扑结构，并显着影响盆地之间的过渡动态。分化和重编程遵循计算景观上的不同转变路径，这应该通过单细胞追踪重编程过程进行实验验证。检查集体组蛋白状态动力学调节对转变动力学和途径的影响，以寻找有效的重编程方案。
Cell reprogramming is a process of transitions from differentiated to pluripotent cell states via transient intermediate states. Within the epigenetic landscape framework, such a process is regarded as a sequence of transitions among basins on the landscape; therefore, theoretical construction of a model landscape which exhibits experimentally consistent dynamics can provide clues to understanding epigenetic mechanism of reprogramming. We propose a minimal gene-network model of the landscape, in which each gene is regulated by an integrated mechanism of transcription-factor binding/unbinding and the collective chemical modification of histones. We show that the slow collective variation of many histones around each gene locus alters topology of the landscape and significantly affects transition dynamics between basins. Differentiation and reprogramming follow different transition pathways on the calculated landscape, which should be verified experimentally via single-cell pursuit of the reprogramming process. Effects of modulation in collective histone state kinetics on transition dynamics and pathway are examined in search for an efficient protocol of reprogramming.