Abstract
The kinase haspin phosphorylates histone H3 at threonine-3 (H3T3ph) during mitosis. H3T3ph provides a docking site for the Chromosomal Passenger Complex at the centromere, enabling correction of erratic microtubule-chromosome contacts. Although this mechanism is operational in all dividing cells, haspin-null mice do not exhibit developmental anomalies, apart from aberrant testis architecture. Investigating this problem, we show here that mouse embryonic stem cells that lack or overexpress haspin, albeit prone to chromosome misalignment during metaphase, can still divide, expand and differentiate. RNA sequencing reveals that haspin dosage affects severely the expression levels of several genes that are involved in male gametogenesis. Consistent with a role in testis-specific expression, H3T3ph is detected not only in mitotic spermatogonia and meiotic spermatocytes, but also in non-dividing cells, such as haploid spermatids. Similarly to somatic cells, the mark is erased in the end of meiotic divisions, but re-installed during spermatid maturation, subsequent to methylation of histone H3 at lysine-4 (H3K4me3) and arginine-8 (H3R8me2). These serial modifications are particularly enriched in chromatin domains containing histone H3 trimethylated at lysine-27 (H3K27me3), but devoid of histone H3 trimethylated at lysine-9 (H3K9me3). The unique spatio-temporal pattern of histone H3 modifications implicates haspin in the epigenetic control of spermiogenesis.
Highlights
The kinase haspin phosphorylates histone H3 at threonine-3 (H3T3ph) during mitosis
In 2004, we have described the reversible phosphorylation of threonine-3 in histone H3 (H3T3ph), a post-translational modification that occurs during mitosis in somatic cells
Analysis of total lysates of KO cells by western blotting revealed the absence of H3T3ph (Fig. 1c, Western blot (WB), lane KO)
Summary
H3T3ph provides a docking site for the Chromosomal Passenger Complex at the centromere, enabling correction of erratic microtubule-chromosome contacts. This mechanism is operational in all dividing cells, haspin-null mice do not exhibit developmental anomalies, apart from aberrant testis architecture. The mark is erased in the end of meiotic divisions, but re-installed during spermatid maturation, subsequent to methylation of histone H3 at lysine-4 (H3K4me3) and arginine-8 (H3R8me[2]). Consistent with a role in CPC recruitment, treatment of somatic cells with haspin-specific inhibitors or knockdown with RNAi causes mobilization of Aurora B from the centromere and partial dispersion to the chromosome arms[11,17,18,19,20]. Apart from chromosome congression, haspin has been implicated in sister-chromatid c ohesion[22,23] and spindle pole a ssembly[24]
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