Participant Support Costs for EFRI CEE: Macrogenomic engineering via modulation of chromatin nanoenvironment #SP0048398

OVERVIEW Title: EFRI CEE: Macrogenomic Engineering via Modulation of Chromatin Nanoenvironment Principal Investigator: Vadim Backman, Ph.D., Walter Dill Scott Professor of Biomedical Engineering, Department of Biomedical Engineering, McCormick School of Engineering and Applied Sciences, Northwestern University Co-Principal Investigators: Igal Szleifer, Ph.D., Christina Enroth-Cugell Professor of Biomedical Engineering, Chemical and Biological Engineering, McCormick School of Engineering and Applied Sciences, Professor of Chemistry, Weinberg College of Arts and Sciences and Professor of Medicine, Northwestern University Hemant K. Roy, M.D., Franz J. Inglefinger Professor of Medicine, Chief, Section of Gastroenterology, Department of Medicine, Boston University Michael Kennedy, Ph.D., Research Professor of Neurobiology, Founding Director of Science in Society, Northwestern University This project converges nanobiophotonics, computational and molecular biology. The main thrust is to build the foundations of macrogenomic engineering (MGE) that will power the ability to modulate the chromatin nanoenvironment for whole-scale transcriptional engineering. This proposal bridges all three EFRI CEE thrusts: nanoscale chromatin imaging, molecular modeling of transcriptional interactions, and transcriptional regulation. INTELLECTUAL MERIT: The adaptive potential of organisms is determined by their capacity to explore their transcriptional landscape of thousands of genes and create new functional states. Currently no platform allows for the predictable transcriptional modulation of this many genes simultaneously. Although epigenetic molecular regulators of individual genes have been identified, largely absent is an understanding of the role of the highly dense and complex physical nanoenvironment within chromatin on transcriptional reactions that govern many genes simultaneously. Transcriptional interactions depend on the local physical nanoenvironment, which in turn, depends on the physical structure of chromatin packing. 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 organization 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 allows cancer cells to survive despite unfavorable conditions (e.g. immune system, chemotherapy) and is a major reason why tumors 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 carcinogenesis and prevent the emergence of resistance to anti-cancer therapeutics. BROADER IMPACTS: Just as the emergence of genetic engineering has provided the power to genetically manipulate cell function, macrogenomic engineering has the potential to power the physical manipulation of living systems and create new strategies for the treatment of disease. In the long-term the project will lead to the emerg