Ki-67 regulates heterochromatin organization in neurons and forms condensates with heterochromatic components

The dysregulation of chromatin organization has been associated with numerous forms of neurological disease. In the ANAPC7 neurodevelopmental syndrome, a disease mechanistically linked to defective proteasomal degradation, the mitotic protein Ki-67 accumulates abnormally in heterochromatin compartments. Here, we investigate Ki-67's role in heterochromatin through in vivo examination of neurons from two relevant genetic mouse models, in vitro assays and computational studies. We find that Ki-67 modulates the size and number of heterochromatin compartments in neurons. Furthermore, we demonstrate that an engineered Ki-67 construct enhances the propensity of HP1α and nucleosome arrays to form condensates in vitro, a process that is mediated through a complex network of electrostatic interactions and is robust to relevant histone post-translational modifications. These observations suggest that Ki-67 may regulate heterochromatin through a phase separation mechanism involving additional heterochromatin components, thus providing insights into the roles of Ki-67 during both typical neurodevelopment and in disease.