Organization and Regulation of Chromatin by Phase Separation

Eukaryotes organize their genetic material into a nucleoprotein filament known as chromatin.  The basic unit of chromatin is the nucleosome, comprised of ~146 base pairs of double stranded DNA wrapped around an octameric assembly of histone proteins.  The nucleosomal unit is highly valent, repeating many thousands to millions of times within the nucleus of eukaryotes.  Histone proteins are modified post-translationally by signaling proteins, regulating access to genomic information by the transcriptional and replicative machinery of the cell.  Dysfunctional regulation of histone post-translational modifications, which play important roles in organismal development, cellular identity, and stimulus response, can result in a variety of cancers. Highly valent biomolecules, like chromatin, can engage in phase separation both in vitro and in cells, modulating their spatial organization and signaling functions. In my project, I aim to use a biochemical reconstitution approach in order to understand the roles that phase separation plays in organizing the genome, focusing especially on the effects of post-translational modification to histone proteins.