RESEARCH - MEMORY
The ability to save the state of a system is a fundamental aspect of many models of computation. This is also fundamental to biological systems, which use memory mechanisms for a wide variety of tasks, including producing the sustained gene expression patterns that drive cell differentiation. Prevailing strategies for engineering memory in synthetic biological systems include: 1) utilizing recombinases to invert the orientation of specific pieces of DNA (DNA rearrangement); 2) constructing positive feedback systems using transcription factors. An additional mechanism for achieving biological memory in eukaryotes is through epigenetic modifications to chromatin. We are comprehensively exploring the genetic design space for cellular memory and building synthetic memory elements in eukaryotic cells, with specific emphasis on developing chromatin-based memory elements and circuits.
With synthetic memory, we can produce biological systems that have the ability to record events, and turn ON/OFF genetic programs without the requirement of a sustained input.
Chromatin is decorated by a large array of biochemical modifications made to DNA and histone proteins. These modifications play key roles in regulating genome structure and function, and some are associated with the establishment of epigenetic memory. In this project, we are developing synthetic chromatin regulators and using them to engineer chromatin-based memory devices in a variety of eukaryotic cells, ranging from yeast to mammalian.
X. Zheng, A. Beyzavi, J. Krakowiak, N. Patel, A. S. Khalil, D. Pincus, "Hsf1 Phosphorylation Generates Cell-to-Cell Variation in Hsp90 Levels and Promotes Phenotypic Plasticity," Cell Reports, vol. 22, iss. 12, 2018.
A. J. Keung and A. S. Khalil, "A Unifying Model of Epigenetic Regulation (Perspective)," Science, vol. 351, iss. 661-662, 2016.
A. J. Keung, J. K. Joung, A. S. Khalil and J. J. Collins, "Chromatin Regulation at the Frontier of Synthetic Biology," Nature Reviews Genetics, vol. 16, iss. 159-171, 2016.
A. J. Keung, C. J. Bashor, S. Kiriakov, J. J. Collins and A. S. Khalil, "Using Targeted Chromatin Regulators to Engineer Combinatorial and Spatial," Cell, vol. 158, iss. 110-120, 2014.
M Park, A. J. Keung and A. S. Khalil, "The Epigenome: The Next Substrate for Engineering," Genome Biology, vol. 17, iss. 183, 2016.
S. Perli*, C. Cui*, T. K. Lu, “Continuous Genetic Recording with Self-Targeting CRISPR-Cas in Human Cells,” Science, published online August 18, 2016, (preprint at bioRxiv, May 20, 2016).