This project tackles the critical question of how epigenetics enable cells with the same genomic DNA to develop into different cell types and respond to environmental cues in different ways. The main objective is to investigate mechanisms whereby epigenetic information controls gene expression by studying the relationship between chemical changes in nucleosomes that package DNA into chromatin, the physical compactness of nucleosomes, and the expression or silencing of genes that ultimately control cellular behavior and fate. The project integrates biochemical and biophysical experimentation, mathematical modeling, and computational analysis, and the outcomes are expected to facilitate "epigenetic engineering" to manipulate cellular states for better understanding and treatment of of human diseases, such as obesity and cancer. The project will also broaden participation of underrepresented groups in engineering by offering research opportunities to high school students in Baltimore, through the Ingenuity project, as well as development of curricular materials and activities supporting K-12 education.
The primary goal of this project is development of a "bottom-up" theoretical, computational, and experimental approach for understanding the physical properties of the epigenome and the physical mechanisms underlying its structure, organization, and function, and for studying their effects on cellular plasticity and phenotypic identity. The focus will be on creating a cohesive model that relates to the physical organization of nucleosomes, interconnects information about epigenetic modifications at the DNA and nucleosomal levels, and predicts higher order chromatin organization, gene expression, and determination of cell state. The research strategy will couple information theory and statistical mechanics with experimental biophysics, chromatin biochemistry and epigenetic biology. Specifically, the mesoscopic chromatin model will be defined by the physical properties of local chromatin deformability and global condensability. Through this "physical" lens, the research will link conventional chromatin biochemistry to large-scale chromosomal organization and lead to experiments for model testing, including imaging analysis at the molecular and cellular level to identify events that drive switching of cell states. The outcomes are expected to relate stochasticity in the information-theoretic epigenetic landscape to pluripotency and changes in cell fate for the first time.
This award is co-funded by the Genetic Mechanisms cluster in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate, and the Emerging Frontiers in Research and Innovation program in the Office of Emerging Frontiers and Multidisciplinary Activities in the Engineering Directorate.
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.
