Ki67 promotes HP1alpha phase separation and regulates heterochromatin domains in ANAPC7 neurodevelopmental syndrome

Genome organization, the packaging and spatial organization of DNA and proteins within thenucleus, is critical to gene regulation and genomic stability. Underscoring this importance,dysregulated chromatin appears to pathologically involved in numerous forms of neurologicaldisease. ANAPC7 neurodevelopmental syndrome is mechanistically linked to defectiveproteasomal degradation, resulting in inappropriate accumulation of Ki-67 in theheterochromatin compartment. Ki-67 is a nuclear protein with roles in chromosome organizationduring mitosis and heterochromatin regulation during interphase. This latter function is poorlyunderstood, and appears to be impactful to the disease-associated context. Here we study the role of Ki-67 in heterochromatin through in vitro assays and in vivo examination of neurons. We findthat Ki-67 modulates the size and number of heterochromatin compartments and their liquid-likebehavior. Furthermore, we demonstrate that Ki-67 can form condensates with chromatin andHP1 alpha, and that disease-relevant post-translational modifications influence the phase separationproperties. These properties provide insight into the heterochromatin-associated function of Ki-67,both in typical neurodevelopment and disorders of neurodevelopment.