VBFF Analog Epigenetic Cell Memory Biology and Engineering
Abstract
The goal of this project is to uncover the molecular underpinnings of analog epigenetic cell memory and to use this knowledge to establish unprecedented engineering capabilities for creating self-organizing and reconfigurable multi-cellular systems with graded cell fates. Epigenetic cell memory enables cells to maintain different phenotypes through distinct gene expression patterns despite a common genotype. DNA methylation and histone modifications are key mediators of long-term maintenance of gene expression states and are believed to occur in an #all or none# fashion, making long-term memory an exclusive attribute of active and silenced gene states. This agrees with the classical view of cell differentiation embodied by the Waddington epigenetic landscape, according to which differentiation progresses in a sequence of binary decisions that either silence or activate genes, leading cells into mutually exclusive gene expression patterns. Surprisingly, and in contrast to current belief, we recently discovered that cells can keep long-term memory of any intermediate gene expression state through graded DNA methylation, which remains practically frozen at the initially set grade. This project thus proposes that epigenetic cell memory can be analog, as opposed to binary, and investigates the extent towhich we can control analog memory with precision for engineering biology.We have three specific objectives. The first objective isto unveil the molecular determinants of analog epigenetic cell memory through a #build-to-understand# approach using our chromosomally integrated reporter system in mammalian cells. The second objective is to establish the engineering capabilities required to precisely modulate analog memory. To achieve this, we propose a hierarchical design in which a #hard# genetic circuit rewires the chromatin modification network to make DNA methylation grade respond to the output of a #soft# genetic circuit that encodes a user-defined gene expression program. The third objective is to establish the engineering foundations required to create multi-cellular systemswith user-defined, persistent, yet reconfigurable, spatial gradients of gene expression, in response to transient environmental stimuli. To this end, we will augment the soft circuits with cell-cell communication modules that link the circuit state of one cell tothat of nearby cells.This project, if successful, will lead to a scientific revolution in biological memory that will open new research avenues in embryonic development and organoids generation. The way in which we understand cell types today will evolve and willopen the possibility for the existence of endless previously unappreciated cell types with yet-to-be-discovered functions. At the same time, the engineering capabilities that we establish here will set the ground for creating new cell types with variegated functionalities that do not currently exist in nature. These capabilities will also reform how we engineer multi-cellular systems, by allowing substantially increased sophistication of the living materials that we can build. Tools for precise modulation of analog epigenetic cell memory will disrupt current DoD-relevant technologies, including the synthesis of complex living materials, organoids, andthe design of interactive biomaterials that sense and store increasingly sophisticated information with minimal power requirement. The outcomes of this project will also enable new technologies of potential interest to the DoD, such as the creation of future human memory organoids. These could be used as a test-bed to study how memories form in the hippocampus, how the speed and quality of learning can be enhanced by external stimulation, and how these properties are affected by extreme conditions such as temperature and radiation. In the long term, these organoids may even open the way to tissue repair and enhancement, by enabling new brain functionsthat today are not possible.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 14, 2024
- Source ID
- N000142512053
Entities
People
- Domitilla Del Vecchio
Organizations
- Massachusetts Institute of Technology
- Office of Naval Research
- United States Navy