Many human diseases result from the dysregulation of the complex interactions between tens to thousands of genes. However, approaches for the transcriptional modulation of many genes simultaneously in a predictive manner are lacking. Here, through the combination of simulations, systems modelling and in vitro experiments, we provide a physical regulatory framework based on chromatin packing-density heterogeneity for modulating the genomic information space. Because transcriptional interactions are essentially chemical reactions, they depend largely on the local physical nanoenvironment. We show that the regulation of the chromatin nanoenvironment allows for the predictable modulation of global patterns in gene expression. In particular, we show that the rational modulation of chromatin density fluctuations can lead to a decrease in global transcriptional activity and intercellular transcriptional heterogeneity in cancer cells during chemotherapeutic responses to achieve near-complete cancer cell killing in vitro. Our findings represent a ‘macrogenomic engineering’ approach to modulating the physical structure of chromatin for whole-scale transcriptional modulation.

许多人类疾病是由于数十至数千个基因之间复杂的相互作用失调导致的。但是，缺乏以预测方式同时转录调节许多基因的方法。在这里，通过模拟，系统建模和体外实验的结合，我们提供了基于染色质堆积密度异质性的物理调控框架，用于调节基因组信息空间。因为转录相互作用本质上是化学反应，所以它们很大程度上取决于局部的物理纳米环境。我们表明染色质纳米环境的调节允许基因表达中的全球模式的可预测的调制。尤其是，我们表明，染色质密度波动的合理调节可导致癌细胞在化学治疗过程中实现近乎完全的体外杀伤反应而降低总体转录活性和细胞间转录异质性。我们的发现代表了一种“宏基因组工程”方法，用于调节染色质的物理结构，以进行全范围的转录调节。