The function of organisms is determined not only by their genes but also by their capacity to express these genes. The adaptive potential of organisms is determined by their capacity to explore their landscape of thousands of genes and create new functional states. Currently no platform allows for the predictable modulation of this many genes simultaneously. The goal of this project is to build the foundations of such a technology, termed macrogenomic engineering. The principles of macrogenomic engineering can be applied to attack the key reason why most currently available anti-cancer treatments fail. In addition to addressing tumor drug resistance this program will impact some of the most significant diseases of the 21st century involving changes in gene expression in Alzheimer's disease and atherosclerosis.
Transcriptional interactions depend on the local physical nanoenvironment, which in turn depends on the three-dimensional structure of the genome. This project will develop physico-chemical methodologies to reversibly manipulate the chromatin nanoenvironment thus affecting transcriptional processes in a predictable manner. This will enable the modulation of the adaptive potential of cells by regulating the degree of freedom within the transcriptome. The first two objectives of the project are to elucidate physico-chemical factors that determine the properties of chromatin packing and the role of the resulting chromatin nanoenvironment in modulating gene networks, intercellular, and temporal transcriptional heterogeneity. The third objective is to apply the principles of macrogenomic engineering to a testbed. The testbed explored in this project is carcinogenesis. Transcriptional diversity is a major reason why tumors eventually develop resistance to most therapies. The project will develop physico-chemical strategies to constrain transcriptional diversity and the adaptive potential of cancer cells in order to prevent the progression of pancreatic and ovarian tumors in animal models and to prevent the emergence of resistance to anti-cancer therapeutics.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
