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Distinct roles of Haspin in stem cell division and male gametogenesis

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

PROVIDER: PRJNA645564 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12199780.fastq.gz	Fastqsanger.gz
	SRR12199781.fastq.gz	Fastqsanger.gz
	SRR12199782.fastq.gz	Fastqsanger.gz
	SRR12199783.fastq.gz	Fastqsanger.gz
	SRR12199784.fastq.gz	Fastqsanger.gz

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

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

2023-08-30 | GSE220824 | GEO

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

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

Function of CHG methylation dynamics in rice male gametogenesis

Project description:In this work, we analyzed DNA methylation in rice male meiocyte, microspore and sperm and studied the function of a set of chromatin regulators during the process. The results indicate that that DNA methylation remodeling started after meiosis of the male meiocytes and that non-CG, particularly CHG, methylation is dynamically remodeling during rice male gametogenesis. The work reveals distinct function of DNA methyltransfesaes and histone demethylase in the remodeling of CHG methylation and suggests that the CHG methylation remodeling has functional significance for male gametogenesis and fertilization.

2023-06-24 | GSE235680 | GEO

DNA methylation dynamic in male rat germ cells during gametogenesis

Project description:To study the dynamic of DNA methylation during male gametogenesis 9 stages of germ cells were purified, then DNA samples (n=4/stage) were analyzed by Rat Methyl seq capture

2023-06-19 | GSE220440 | GEO

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

Function of CHG methylation dynamics in rice male gametogenesis

Project description:Function of CHG methylation dynamics in rice male gametogenesis

| PRJNA986895 | ENA

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

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