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

Abstract

Abstract 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.