Almassalha Luay M, Bauer Greta M, Wu Wenli, Cherkezyan Lusik, Zhang Di, Kendra Alexis, Gladstein Scott, Chandler John E, VanDerway David, Seagle Brandon-Luke L, Ugolkov Andrey, Billadeau Daniel D, O'Halloran Thomas V, Mazar Andrew P, Roy Hemant K, Szleifer Igal, Shahabi Shohreh, Backman Vadim
Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA.
Department of Obstetrics and Gynecology, Prentice Women's Hospital, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA.
Nat Biomed Eng. 2017 Nov;1(11):902-913. doi: 10.1038/s41551-017-0153-2. Epub 2017 Nov 6.
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.
许多人类疾病源于数十至数千个基因之间复杂相互作用的失调。然而，目前缺乏以预测方式同时对许多基因进行转录调控的方法。在这里，通过模拟、系统建模和体外实验相结合，我们提供了一个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。由于转录相互作用本质上是化学反应，它们在很大程度上取决于局部物理纳米环境。我们表明，对染色质纳米环境的调控能够对基因表达的全局模式进行可预测的调节。特别是，我们表明，在化疗反应过程中，对染色质密度波动的合理调节可导致癌细胞中全局转录活性和细胞间转录异质性的降低，从而在体外实现近乎完全的癌细胞杀伤。我们的研究结果代表了一种“宏基因组工程”方法，用于调节染色质的物理结构以进行全规模的转录调控。
