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Haspin regulates mouse embryonic stem cell developmental potencies through Wnt5a mediated asymmetric cell division

ABSTRACT: To investigate the function of Haspin in the mouse embryonic stem cell, we established Haspin knockout cell lines.

ORGANISM(S): Mus musculus

PROVIDER: GSE220824 | GEO | 2023/08/30

REPOSITORIES: GEO

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Haspin regulates mouse embryonic stem cell developmental potencies through Wnt5a mediated asymmetric cell division

Project description:Haspin regulates mouse embryonic stem cell developmental potencies through Wnt5a mediated asymmetric cell division

| PRJNA911679 | ENA

Haspin balances the ratio of asymmetric cell division through Wnt5a and regulates cell fate decisions in mouse embryonic stem cells.

Project description:Many different types of stem cells utilize asymmetric cell division (ACD) to produce two daughter cells with distinct fates. Haspin-catalyzed phosphorylation of histone H3 at Thr3 (H3T3ph) plays important roles during mitosis, including ACD in stem cells. However, whether and how Haspin functions in ACD regulation remains unclear. Here, we report that Haspin knockout (Haspin-KO) mouse embryonic stem cells (mESCs) had increased ratio of ACD, which cumulatively regulates cell fate decisions. Furthermore, Wnt5a is significantly downregulated due to decreased Pax2 in Haspin-KO mESCs. Wnt5a knockdown mESCs phenocopied Haspin-KO cells while overexpression of Wnt5a in Haspin-KO cells rescued disproportionated ACD. Collectively, Haspin is indispensable for mESCs to maintain a balanced ratio of ACD, which is essential for normal development and homeostasis.

| S-EPMC10447528 | biostudies-literature

Distinct roles of Haspin in stem cell division and male gametogenesis

Project description:The atypical protein kinase Haspin phosphorylates Histone H3 at threonine-3 (H3T3ph) during mitosis. H3T3ph creates a docking site for the Chromosomal Passenger Complex at the inner centromere, enabling correction of erratic microtubule-chromosome contacts and preventing chromosome mis-segregation. Surprisingly, Haspin knockout in the mouse does not cause developmental defects, except for testicular anomalies. Therefore, the physiological role of this kinase and the mechanistic significance of H3T3ph are in question. We show here that mouse embryonic stem cells that lack or overexpress Haspin are prone to chromosome misalignment. However, the cell population as a whole maintains the ability to expand and differentiate into multiple lineages. Although not essential for pluripotency, Haspin affects the expression of several testis-specific genes. Furthermore, the H3T3ph mark is detected in under-condensed chromatin domains of haploid spermatids, in cis with lysine/arginine methylation marks. We propose that Haspin controls a compound phospho-methyl switch and regulates testis-specific transcription.

2021-10-06 | GSE154246 | GEO

Distinct roles of Haspin in stem cell division and male gametogenesis

Project description:Distinct roles of Haspin in stem cell division and male gametogenesis

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Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML

Project description:Acute Myeloid Leukemia (AML) is a blood cancer complicated by acquired drug resistance, disease relapse, and low overall survival rates. Combination therapies using multiple targeted inhibitors can effectively treat AML patients. However, combination treatments are limited by the number of useable targets and our ability to create rational pairings using complimentary molecular mechanisms. Here, we used a human kinase domain-targeted CRISPR screen to identify histone H3 associated protein kinase (HASPIN) as a significant, understudied dependency in AML. HASPIN depletion significantly reduced growth rate, induced a cell cycle arrest, and dysregulated transcription in AML. A proteomics datamining study characterized splicing factors as major HASPIN kinase substrates and highlighted HASPIN’s role as a splicing regulatory kinase. Accordingly, HASPIN depletion strongly dysregulated splicing and inversed aberrant, pro-leukemic splicing programs in AML patients. HASPIN inhibitor CHR-6494 effectively reduced cell viability across AML subtypes while sparing healthy cells. Furthermore, a novel combination therapy consisting of CHR-6494 and BCL-2 inhibitor Venetoclax synergistically reduced AML cell viability and resensitized Venetoclax-resistant AMLs to treatment. Our study presents HASPIN kinase as a novel, therapeutic target for AML, underscores an underappreciated role in splicing regulation, and proposes a viable combination treatment for clinical use.

2025-08-04 | GSE281301 | GEO

Asymmetric Division in a Two-Cell-Like State Rejuvenates Embryonic Stem Cell Lineage

Project description: Not available

| S-BSST1340 | biostudies-other

Genomic distribution of the cohesin subunit Stromalin (SA) in wild-type and Haspin knock-down Drosophila melanogaster Kc167 cells

Project description:Haspin is required for Drosophila SA binding to chromatin Keywords: Genome binding/occupancy profiling by high throughput sequencing

2022-07-02 | GSE118813 | GEO

Distinct roles of haspin in stem cell division and male gametogenesis.

Project description: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.

| S-EPMC8494884 | biostudies-literature

Haspin-dependent and independent effects of the kinase inhibitor 5-Iodotubercidin on self-renewal and differentiation.

Project description:The kinase Haspin phosphorylates histone H3 at threonine-3 (H3T3ph), creating a docking site for the Chromosomal Passenger Complex (CPC). CPC plays a pivotal role in preventing chromosome misalignment. Here, we have examined the effects of 5-Iodotubercidin (5-ITu), a commonly used Haspin inhibitor, on self-renewal and differentiation of mouse embryonic stem cells (ESCs). Treatment with low concentrations of 5-ITu eliminates the H3T3ph mark during mitosis, but does not affect the mode or the outcome of self-renewal divisions. Interestingly, 5-ITu causes sustained accumulation of p53, increases markedly the expression of histone genes and results in reversible upregulation of the pluripotency factor Klf4. However, the properties of 5-ITu treated cells are distinct from those observed in Haspin-knockout cells generated by CRISPR/Cas9 genome editing, suggesting "off-target" effects. Continuous exposure to 5-ITu allows modest expansion of the ESC population and growth of embryoid bodies, but release from the drug after an initial treatment aborts embryoid body or teratoma formation. The data reveal an unusual robustness of ESCs against mitotic perturbants and suggest that the lack of H3T3ph and the "off-target" effects of 5-ITu can be partially compensated by changes in expression program or accumulation of suppressor mutations.

2020-01-16 | GSE119737 | GEO

NOTCH maintains developmental cardiac gene network through WNT5A.

Project description:NOTCH and WNT signaling pathways play critical roles in cardiac chamber formation. Here we explored the potential interactions between the two pathways in this developmental process by using genetically modified mouse models and whole embryo culture systems. By deletion of Notch1 to inactivate NOTCH1 signaling in the endocardium in vivo and ex vivo rescue experiments, we showed that myocardial WNT5A mediated endocardial NOTCH1 signaling to maintain the gene regulatory network essential for cardiac chamber formation. Furthermore, genetic deletion of β-catenin in the myocardium and inhibition of the WNT/Ca2+ signaling by FK506 resulted in a similar disruption of the gene regulatory network as inactivation of endocardial NOTCH1 signaling. Together, these findings identify WNT5A as a key myocardial factor that mediates the endocardial NOTCH signaling to maintain the gene regulatory network essential for cardiac chamber formation through WNT/β-catenin and WNT/Ca2+ signaling pathways.

| S-EPMC9531535 | biostudies-literature

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