When cells divide, not only the genetic sequence but also the chemical additions to the DNA and its three-dimensional organization (the so-called epigenome) must be replicated. The epigenome plays a central role in controlling the activity levels of individual genes within a cell, and correct replication is critically important for maintaining cellular function from one cell generation to the next. Through a combination of genomics, microscopy, and computational modeling, this project seeks to uncover the molecular and physical principles of epigenome replication. The results are expected to open new opportunities for cellular engineering. This project will broaden participation in research at the crossroads of molecular biology, applied mathematics, and data-science for high school and undergraduate students, with an emphasis on recruitment and training of students from underrepresented groups. In addition, the project will expand access to science education through a unique program for middle- and high-school students in hospital settings.

Temporal variation over the cell cycle is an under-appreciated source of heterogeneity in the epigenetic landscape and an under-utilized mechanism of control in epigenome engineering. This project will characterize how sub-cell cycle dynamics in DNA and histone methylation after replication direct the physical compaction and phase separation of chromatin to ultimately drive both the activation of genes during stem cell differentiation and the divergence of epigenetic patterns observed across multiple cell generations. The project will establish whether temporal heterogeneity in DNA and/or histone methylation operates as a critical feature of mammalian life that either facilitates cell state-transitions, leads to error accumulation and drift in the regulatory landscape of cells, or both. In addition to advancing the fundamental understanding of epigenome regulation and dynamics, the project will deliver: predictive models rooted in polymer physics theory and biomolecular kinetics, which will unify mechanistic principles with ‘omic-scale datasets, and novel tools (biochemical, genetic, and optical) for measuring and perturbing epigenome dynamics, thereby advancing the fields of developmental biology, biotechnology, and biophysics/mathematical biology.

This project is funded by the Understanding the Rules of Life: Epigenetics Program, administered as part of NSF's Ten Big Ideas through the Division of Emerging Frontiers in the Directorate for Biological Sciences. Co-funding is provided by the Genetic Mechanisms Program, Division of Molecular and Cellular Biosciences, Directorate for Biological Sciences.

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.

National Science Foundation (NSF)
Emerging Frontiers (EF)
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Karen Cone
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University of California Irvine
United States
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