In each human cell, the genome is tightly packaged into a complex called chromatin by wrapping the DNA around spool-like protein cylinders to fit inside the nucleus. Both the DNA and protein components of chromatin can be modified in the nucleus to produce "chemical bookmarks." Cells can use these bookmarks, together with the information in the sequence of bases in the DNA, as instructions for switching genes on and off at the right time and in the right place. How chemical bookmarks work is still unclear, but some studies have shown that misplaced bookmarks can contribute to the onset of different diseases. The goal of this project is to understand how chemical bookmarks function. The strategy will be to use synthetic biology to reprogram the bookmarks at desired regions of the DNA to change their switching behavior. This will help reveal how DNA bookmarking controls the fate and function of different cells. The work will have educational impact by integrating students and scientists from engineering, computer sciences, chemistry and biology to uncover the principles by which information stored in chromatin is used to make different cell types and govern their function. The outcomes could have broader societal impact by contributing to development of methods for correcting disease-associated bookmarking errors, or by using synthetic switches to protect against organisms with DNA-based genomes - such as engineered viruses, bacteria and other pathogens - that may pose biological threats.
The central goal of this transformative and transdisciplinary project is to create nanoscale so-called "epigenetic switches" that can sculpt the chromatin nano-environment at targeted genomic loci. This class of 2nm-scale switches can be programmed to rewire epigenetic states at specified loci and evoke informative and meaningful phenotypic outcomes. These epigenetic switches are composed of synthetic DNA binding polyamide molecules that can be programmed to target genomic sites embedded in diverse chromatin states. Moreover, using modular design, these synthetic genome readers can be conjugated to different small molecule ligands that mimic epigenetic signals or engage distinct cellular machines to rewire overlaid chromatin or epigenetic states. The foundational technology to be developed has wide-ranging broader impacts on: (i) elucidating "Rules of Life" that govern genome architecture, stability, and the regulated access to genomic information, (ii) revealing new principles of epigenome or chromatin organization, (iii) epigenetic engineering of living systems, and (iv) innovative genome-targeted therapeutics.
This award was jointly funded by the Emerging Frontiers in Research and Innovation Program in the Division of Emerging Frontiers and Multidisciplinary Activities in the Engineering Directorate, by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate, and by the Chemistry of Life Processes Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate.
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.
