HASPIN kinase mediates histone deacetylation to regulate oocyte meiotic maturation in pigs

Abstract

HASPIN kinase-catalyzed phosphorylation of histone H3 on threonine 3 (H3T3p) directs the activity and localization of chromosomal passenger complex (CPC) and spindle assembly checkpoint (SAC) to regulate chromosome condensation and segregation in both mitosis and meiosis. However, the function of HASPIN kinase in the meiotic maturation of porcine oocytes is not yet known. Here, we found that HASPIN mRNA is constantly expressed in porcine oocyte maturation and subsequent early embryo development. H3T3p is highly enriched on chromosomes at germinal vesicle breakdown (GVBD) stage and thereafter maintains a low level in progression through metaphase I (MI) to metaphase II (MII). Correspondingly, H3T3p was completely abolished in oocytes treated with an inhibitor of HASPIN kinase. Functionally, inhibition of HASPIN activity led to a significant reduction in the rate of oocyte meiotic maturation and the limited cumulus expansion. Additionally, HASPIN inhibition caused both spindle disorganization and chromosome misalignment in oocytes at MI and MII stage. Importantly, HASPIN inhibition severely prevented deacetylation of several highly conserved lysine (K) residues of histone H3 and H4 including H3K9, H3K14, H4K5, H4K8, H4K12 and H4K16 on the metaphase chromosomes during oocyte meiotic maturation. Taken together, these results demonstrate that HASPIN kinase regulates porcine oocyte meiotic maturation via modulating histone deacetylation.

Haspin participates in Aurora phosphorylation at centromeres and contributes to chromosome congression in male mouse meiosis

“…Chemical inhibition of Haspin by 5-Itu causes cell instability and clustering defects of acentriolar MTOCs in meiosis-I (Balboula et al, 2016). This evolutionary conserved functions of Haspin kinases in mammals have recently been also reported in pig oocytes (Cao et al, 2019). However, much fewer reports have been presented for spermatogenesis, where recent data have suggested that the unique spatio-temporal pattern of histone H3 modifications implicates Haspin in the epigenetic control of spermiogenesis (Soupsana et al, 2021).…”

Pervasiveness of intronless genes expressed in haploid germ cell differentiation

“…Prevalence of singlenucleotide polymorphisms (SNPs) in SCOT-T in infertile or proven fertile populations oocyte meiotic maturation. 32 HASPIN is also slightly expressed in somatic cells, where it phosphorylates histone H3 threonine 3 and plays an important role in chromosomal distribution during cell division. 33 However, no specific phenotype was observed in HASPIN gene-disrupted mice.…”

“…HASPIN is another characteristic intronless gene of interest 31 . HASPIN is predominantly expressed in male germ cells and regulates oocyte meiotic maturation 32 . HASPIN is also slightly expressed in somatic cells, where it phosphorylates histone H3 threonine 3 and plays an important role in chromosomal distribution during cell division 33 .…”

HASPIN kinase inhibitor CHR-6494 suppresses intestinal polyp development, cachexia, and hypogonadism in Apc min/+ mice

“…HASPIN has been suggested to phosphorylate histone H3 at threonine 3 in mitotic cells ( Dai et al , 2005 ; Dai and Higgins, 2005 ). HASPIN is found in the centrosomes and spindles during mitosis, where it integrates the regulation of chromosome and spindle function during mitosis and meiosis ( Yu et al , 2017 ; Cao et al , 2019 ). Recently, HASPIN was detected during phosphorylation of threonine 127 on TH2A, a germ cell-specific H2A variant, in condensed spermatids and mitotic early preimplantation mouse embryos ( Hada et al , 2017 ).…”