Science and Engineering

University of California, Santa Barbara

Omar Saleh, Enoch Yeung
Santa Barbara, CA
$1,000,000
December 2019
 

Chromatin packaging, on multiple scales, is now understood to be driven in part by liquid-liquid phase transitions, typically involving droplets of biomolecules that surround and sequester genomic segments.  Further, the phase separations are themselves regulated by genetic outputs.  Phase transitions differ strongly from classic biomolecular interactions, exhibiting discontinuous responses to solution changes and unique dynamics (e.g. nucleation).  How these phenomena affect regulation is an open question.  These investigators will illuminate this issue using a synthetic chromatin system consisting of self-assembled DNA particles that phase separate to form droplets.  The DNA liquid will be interfaced with a gene such that liquid formation modulates transcription, while the transcribed RNA modulates liquid stability.  The resulting feedback network will permit chromatin-like phase-based autoregulation in a well-controlled model system.  The researchers will exploit this genetically-controlled phase behavior to create oscillating or self-patterning systems.  Experiments will use multi-modal methods to track the dynamics of several molecular parameters across many system designs.  Results will be analyzed using biophysical models that predict behavior based on known molecular mechanisms, and unbiased machine-learning models that exploit the broad data set, allowing for the discovery of unexpected mechanisms.  The result will be the development of validated concepts describing the interplay of genetics and phase transitions that can be applied to other systems.  This project could transform our understanding of chromatin structure-forming processes; to establish the unique abilities of phase-transition dynamics within a systems biology framework; and to define a novel direction in synthetic biology and biomaterials.

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