Abstract
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 in Drosophila melanogaster and 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.
Highlights
Genome organization in the cell nucleus plays an important role in the regulation of gene expression during cellular differentiation and development [1,2]
Our analyses showed that Drosophila haspin is necessary for insulator activity, nuclear architecture, heterochromatin organization and pairing-sensitive gene silencing
We further found that haspin modulates Pds5cohesin association with chromatin and it is required for robust Polycomb-mediated homeotic gene silencing
Summary
Genome organization in the cell nucleus plays an important role in the regulation of gene expression during cellular differentiation and development [1,2]. Insulator or architectural proteins are essential components of the three-dimensional organization of chromatin by mediating long-range interactions between distant sites in the genome. Long-range gene regulation involves epigenetic components such as the Polycomb group proteins (PcG) [7,8,9,10,11]. Precise spatiotemporal expression of Hox genes involves an intricate collection of enhancers, promoters, polycomb response elements (PREs) and insulators. It has been demonstrated, both by fluorescent in situ hybridization and Chromosome Conformation Capture approaches, that chromatin organization of the Abdominal-B (Abd-B) locus in the bithorax complex (BX-C) is a critical determinant of the regulation of the expression of the gene. Several reports have shown that insulators and PREs interact with the Abd-B promoter in tissues where the gene is not expressed, and Polycomb and the insulator/architectural proteins CTCF and CP190 are required for these interactions [12,13,14,15]
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