Haspin kinase modulates nuclear architecture and Polycomb-dependent gene silencing

Author summary Haspin is a highly conserved kinase in eukaryotes involved in chromosome organization during mitosis. In this study we demonstrated that haspin is also required to maintain proper chromatin organization during interphase. Our analyses showed thatDrosophilahaspin is necessary for insulator activity, nuclear architecture, heterochromatin organization and pairing-sensitive gene silencing. We further found that haspin modulates Pds5-cohesin association with chromatin and it is required for robust Polycomb-mediated homeotic gene silencing. Overall our findings reveal that haspin kinase is a key element in chromatin organization and thereby regulates gene expression. Haspin, a highly conserved kinase in eukaryotes, has been shown to be responsible for phosphorylation of histone H3 at threonine 3 (H3T3ph) during mitosis, in mammals and yeast. Here we report that haspin is the kinase that phosphorylates H3T3 inDrosophila melanogasterand it is involved in sister chromatid cohesion during mitosis. Our data reveal that haspin also phosphorylates H3T3 in interphase. H3T3ph localizes in broad silenced domains at heterochromatin and lamin-enriched euchromatic regions. Loss of haspin compromises insulator activity in enhancer-blocking assays and triggers a decrease in nuclear size that is accompanied by changes in nuclear envelope morphology. We show that haspin is a suppressor of position-effect variegation involved in heterochromatin organization. Our results also demonstrate that haspin is necessary for pairing-sensitive silencing and it is required for robust Polycomb-dependent homeotic gene silencing. Haspin associates with the cohesin complex in interphase, mediates Pds5 binding to chromatin and cooperates with Pds5-cohesin to modify Polycomb-dependent homeotic transformations. Therefore, this study uncovers an unanticipated role for haspin kinase in genome organization of interphase cells and demonstrates that haspin is required for homeotic gene regulation.