Author: Lifeng Chen

Genome Organization through Chromatin Phase Separation

Membraneless compartments are involved in almost all major functions in the nucleus. These forms of organization often occur through liquid-liquid phase separation (LLPS) of key proteins, and they act on the genome to regulate transcription, repression, repair, and maintenance. However, some recent data argue that the genome is not a passive scaffold as these models suggest. Instead, chromatin has intrinsic phase separation capability and can actively modulate its own biophysical properties. Strikingly, LLPS propensity of synthetic chromatin arrays depend on their nucleosomal linker lengths, and the condensates formed exhibit different dynamics and density. I am continuing to explore how linker lengths dictate chromatin LLPS and higher order structure. I am also interested in how cells can take advantage of these divergent properties in regulating gene expression and genome organization.

The centromere is critical for the faithful segregation of chromosomes during cell division as it mediates the connection between the DNA and the spindle. For most organisms, the centromere is epigenetically defined by the presence of nucleosomes containing a histone H3 variant, CENP-A. Although these CENP-A nucleosomes are sparse compared to nucleosomes that contain histone H3, they cluster across megabases to form a single compact kinetochore. I am interested in how phase separation of centromeric chromatin in conjunction with kinetochore proteins organize to achieve this feat. Furthermore, in humans, the centromere is typically situated onto DNA sequences composed of regular repeats of 171bp monomers. Thus, it is analogous to the regularly spaced synthetic chromatin arrays and serves as a promising model to test the function of defined linker lengths in cells.