Collaborative Research: MODULUS: Uncovering and re-engineering chromatin modification circuits that dictate epigenetic cell memory

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The different cell types that make up our body, such as skin cells or blood cells, have the ability to maintain distinct identities for the lifetime of an individual even if they all have the same DNA. How is memory of cell’s identity safeguarded for an individual’s lifetime? This project uncovers key molecular interaction circuits that enable the same DNA sequence to give rise to distinct and concurrent long-term cellular identities. This knowledge is valuable to understand diseases linked to loss of cell identity, such as cancer, to educate new approaches to stem cell reprogramming, and, ultimately, to program human cells for cell therapy. This project involves creating and analyzing mathematical models of molecular circuits that alter DNA compaction. These mathematical models enrich current educational curricula in quantitative molecular biology, systems biology, and synthetic biology. Graduate students receive a highly interdisciplinary training grounded on molecular biology, mathematical modeling, and mathematical theory of stochastic processes. Education aspects of the project impact K-12 and undergraduate students, members of underrepresented groups in science and women in mathematics through outreach and curriculum development activities. The objective of this project is to uncover fundamental principles by which chromatin modification circuits mediate epigenetic cell memory (ECM). ECM is the ability of cells to maintain distinct cell-type-specific gene expression patterns through subsequent cell divisions without a change in genetic sequence. The key hypothesis of this project is that synergistic positive feedback loops within chromatin modification circuits govern ECM in combination with time scale separation between epigenetic erasure and read-write processes. To validate this hypothesis, this project follows a “build-to-understand” approach driven by rigorous mathematical analysis of the (quasi)-stationary probability distribution of new multi-time scale stochastic processes. These processes naturally arise from the dynamics of chromatin modification circuits and take the form of small perturbations of non-ergodic processes, that capture time scale separation. The project has three aims. Aim 1 and Aim 2 focus on a single gene’s chromatin modification circuit, identifies biochemical parameters that control time scale separation, and establish an experimental model system to tune them. Aim 2 is focused on the extent to which DNA methylation biases ECM towards a repressed chromatin state and proposes a positive autoregulation mechanism to enhance ECM of an active chromatin state. Aim 3 investigates how, by wiring multiple genes’ chromatin modification circuits together, a long-term memory of arbitrary gene expression patterns could be created. As a proof of principle, Aim 3 performs experiments on an epigenetic toggle switch test-bed, a motif highly represented in gene regulatory networks involved in cell fate determination, in which two gene mutually repress each other. This project is co-funded by the Systems and Synthetic Biology and Genetic Mechanisms clusters in the Division of Molecular and Cellular Biosciences, the Mathematical Biology program in the Division of Mathematics and the Cellular and Biochemical Engineering program in the Division of Chemical, Bioengineering, Environmental and Transport Systems.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.