Understanding and Re-engineering Epigenetic Cell Memory: A Theory-driven Approach
Abstract
Epigenetic cell memory (ECM), the ability of multi-cellular organisms to record transient environmental stimuli into heritable gene expression states without changes in genetic sequence, remains one of the most puzzling questions in modern biology. At the same time, reengineering epigenetic cell memory would offer unprecedented opportunities from re-constructing the environment to which an individual has been exposed, to enabling on-demand, patient-specific wound healing and tissue repair. Chromatin state, determined by histone modifications and DNA methylation, has appeared as a key mediator of ECM, However, the fundamental principles of this mediation remain elusive. Research has been driven by experiments characterizing readers, writers, and erasers of chromatin modifications and a wealth of knowledge is available on these. By contrast, an understanding of the dynamics of interactions among these molecular players and their target modifications has been lagging behind. Yet, it is most likely this network of interactions, as opposed to the molecular players alone, that dictates ECM. Here, we propose to use the large bulk of data available in the literature on the properties of readers, writers, and erasers of chromatin modifications to tease out the interaction network among these players and their target histone/DNA modifications. We propose to mathematically analyze the dynamics of this network to extract the governing principles by which chromatin regulatory circuits mediate ECM. With this knowledge, we propose to reengineer chromatin modification circuits to demonstrate our ability to control ECM of active and repressed gene states. The governing principles linking chromatin state and ECM that we will uncover and the reengineered chromatin modification circuits that we will create will empower us with unprecedented tools to both reconstruct environmental cues from our epigenome and to control cell fate decisions for therapeutic applications.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 07, 2021
- Source ID
- HQ00342010032
Entities
People
- Domitilla Del Vecchio
Organizations
- Massachusetts Institute of Technology
- Office of the Secretary of Defense
- Washington Headquarters Services