A deterministic map of Waddington's epigenetic landscape for cell fate specification.
A deterministic map of Waddington's epigenetic landscape for cell fate specification.
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DOI：
10.1186/1752-0509-5-85
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发表时间：
2011-05-27
影响因子：
--
通讯作者：
Andersen ME
中科院分区：
文献类型：
--
作者：
Bhattacharya S;Zhang Q;Andersen ME
“表观遗传图景”的图像中有一系列分叉的山谷和脊线，描绘了稳定的细胞状态和这些状态之间的障碍，这是对细胞谱系指定的一个流行的视觉隐喻--特别是考虑到最近的发现，终末分化的成年细胞可以重新编程为多能干细胞或替代细胞谱系。然而，表观遗传格局能否被定量地绘制出来，以提供细胞分化的预测模型，这个问题在很大程度上仍然没有答案。在这里，我们基于调控细胞命运的基因网络的动力学参数，导出了一个简单的确定性路径积分准势，并证明了这个量在基因网络状态空间中的时间轨迹上是最小化的，从而为细胞分化过程提供了一个方向性的标志。然后，我们使用得到的准势作为“高度”的量度来定量绘制表观遗传地貌，在该地貌上，轨迹从任何位置“下坡”。随机模拟证实，这一计算景观的海拔与特定细胞命运发生的可能性相关，人口稠密的低洼“谷”代表稳定的细胞状态，较高的“脊”充当稳定状态之间转换的障碍。这张细胞命运选择背后的表观遗传图景的量化地图提供了对在生理发育背景下以及在人工诱导的细胞谱系重新编程期间指导细胞分化的“力”的机械性洞察。我们绘制景观图的通用方法适用于无法推导出解析势函数的非梯度基因调控系统，也适用于高维基因网络。严格量化控制细胞谱系选择的基因调控电路，并随后绘制表观遗传图谱，可能有助于确定细胞命运重新编程的最佳路线。
The image of the "epigenetic landscape", with a series of branching valleys and ridges depicting stable cellular states and the barriers between those states, has been a popular visual metaphor for cell lineage specification - especially in light of the recent discovery that terminally differentiated adult cells can be reprogrammed into pluripotent stem cells or into alternative cell lineages. However the question of whether the epigenetic landscape can be mapped out quantitatively to provide a predictive model of cellular differentiation remains largely unanswered. Here we derive a simple deterministic path-integral quasi-potential, based on the kinetic parameters of a gene network regulating cell fate, and show that this quantity is minimized along a temporal trajectory in the state space of the gene network, thus providing a marker of directionality for cell differentiation processes. We then use the derived quasi-potential as a measure of "elevation" to quantitatively map the epigenetic landscape, on which trajectories flow "downhill" from any location. Stochastic simulations confirm that the elevation of this computed landscape correlates to the likelihood of occurrence of particular cell fates, with well-populated low-lying "valleys" representing stable cellular states and higher "ridges" acting as barriers to transitions between the stable states. This quantitative map of the epigenetic landscape underlying cell fate choice provides mechanistic insights into the "forces" that direct cellular differentiation in the context of physiological development, as well as during artificially induced cell lineage reprogramming. Our generalized approach to mapping the landscape is applicable to non-gradient gene regulatory systems for which an analytical potential function cannot be derived, and also to high-dimensional gene networks. Rigorous quantification of the gene regulatory circuits that govern cell lineage choice and subsequent mapping of the epigenetic landscape can potentially help identify optimal routes of cell fate reprogramming.
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影响因子：
--
作者：
Cao, Youfang;Liang, Jie
通讯作者：
Liang, Jie
影响因子：
21.3
作者：
Shen, CN;Slack, JMW;Tosh, D
通讯作者：
Tosh, D
DOI：
10.1073/pnas.040411297
发表时间：
2000-02-29
影响因子：
11.1
作者：
Hasty, J;Pradines, J;Collins, JJ
通讯作者：
Collins, JJ
影响因子：
64.5
作者：
Hanna, Jacob;Markoulaki, Styliani;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf
捕食者猎物网络的潜在景观和概率通量
影响因子：
3.7
作者：
Li C;Wang E;Wang J
通讯作者：
Wang J