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HnRNPR regulates alternative splicing in an m6A-dependent manner required for spermiogenesis and male fertility in humans and mice

ABSTRACT: Male infertility is an increasingly pressing global health concern, with abnormal spermiogenesis being a major cause of asthenoteratozoospermia. Although RNA-binding proteins (RBPs)-orchestrated alternative splicing has recently garnered significant attention, its regulation mechanisms during spermiogenesis remain unclear. Here, we identify hnRNPR as a crucial m6A-dependent splicing regulator. Mutations in hnRNPR lead to asthenoteratozoospermia in both humans and mice. Mechanistically, loss of hnRNPR exhibits widespread transcriptomic, proteomics, and m6A-modified splicing dysregulation, disrupting these genes essential for acrosome formation and flagellum development. Remarkably, Skap2 knockdown mice exhibit sperm defects that phenocopy those seen in Hnrnpr mutants. Importantly, therapeutic delivery of SKAP2, via extracellular vesicles, restores F-actin-mediated cytoskeletal integrity and improves sperm motility. Collectively, these findings establish that spermiogenesis is controlled post-transcriptionally by splicing in an m6A-dependent manner and reveal a promising therapeutic contribution for male infertility.

INSTRUMENT(S): LTQ

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Testis, Sperm

DISEASE(S): Disease Free

SUBMITTER: 世明甘

LAB HEAD: shiming gan

PROVIDER: PXD064447 | Pride | 2025-06-10

REPOSITORIES: Pride

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hnRNPR regulates alternative splicing in an m6A-dependent manner required for spermiogenesis and male fertility in humans and mice

Project description:Male infertility is an increasingly pressing global health concern, with abnormal spermiogenesis being a major cause of asthenoteratozoospermia. Although RNA-binding proteins (RBPs)-orchestrated alternative splicing has recently garnered significant attention, its regulation mechanisms during spermiogenesis remain unclear. Here, we identify hnRNPR as a crucial m6A-dependent splicing regulator. Mutations in hnRNPR lead to asthenoteratozoospermia in both humans and mice. Mechanistically, loss of hnRNPR exhibits widespread transcriptomic, proteomics, and m6A-modified splicing dysregulation, disrupting these genes essential for acrosome formation and flagellum development. Remarkably, Skap2 knockdown mice exhibit sperm defects that phenocopy those seen in Hnrnpr mutants. Importantly, therapeutic delivery of SKAP2, via extracellular vesicles, restores F-actin-mediated cytoskeletal integrity and improves sperm motility. Collectively, these findings establish that spermiogenesis is controlled post-transcriptionally by splicing in an m6A-dependent manner and reveal a promising therapeutic contribution for male infertility.

2025-06-04 | PXD064452 | Pride

Gcn5-mediated histone acetylation governs nucleosome dynamics in spermiogenesis [ATAC-seq]

Project description:During mammalian spermatogenesis, male germ cells undergo dramatic reorganization of chromatin, whereby 90-99% of histones are evicted and replaced by protamines. This reorganization prominently features histone acetylation to loosen chromatin structure. Given the potential role of retained histones in fertility and early embryonic development, the genomic location of retained nucleosomes is of great interest. However, the ultimate position and mechanisms underlying nucleosome eviction/retention are poorly understood, including several studies utilizing MNase-seq methodologies, but reporting remarkably dissimilar locations. Here, we utilized ATAC-seq to determine the location of retained nucleosomes in mouse sperm and found enrichment at promoters, but also retention at inter- and intragenic regions, and repetitive elements. We further investigated nucleosome eviction/retention by generating pre-meiotic, germ cell specific, conditional knockout mice for the histone acetyltransferase Gcn5, a key histone acetyltransferase. Gcn5cKO germ cells exhibited abnormal chromatin dynamics during spermiogenesis, including diminished nucleosome eviction leading to increased histone retention in sperm. These mice exhibited severe reproductive phenotypes: abnormal sperm production, sperm morphology, and ultimately, male infertility. Our findings demonstrate Gcn5 mediated histone acetylation promotes chromatin accessibility and nucleosome eviction in spermiogenesis, and that loss of histone acetylation leads to defects that disrupt male fertility and potentially, early embryogenesis.

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Gcn5-mediated histone acetylation governs nucleosome dynamics in spermiogenesis [MNase-Seq]

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Gcn5-mediated histone acetylation governs nucleosome dynamics in spermiogenesis [RNA-Seq]

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Hipk4 is a manchette-associated protein essential for spermiogenesis

Project description:Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility, characterized by the absence of spermatozoa in the ejaculate. The etiology and genetic mechanism(s) of this disease remain largely unclear. Using Sanger sequence, we identified 12 heterozygous missense mutations and 2 heterozygous nonsense mutations in the HIPK4, encoding a serine/threonine kinase. Moreover, K490* mutant cause HIPK4 unstable in 293T cells. In accord with these findings, we observed that homozygous Hipk4-/- male mice were infertility owing to malformed and immotile spermatozoa, which are characterized by a deformed nucleus and a detached acrosome. Furthermore, we performed a phosphoproteomic analysis of testis from Hipk4 wild type and knockout mice, revealing multiple targets regulated by Hipk4 during spermiogenesis. Notably, manchette-associated protein Rimbp3 has multiple phosphorylation sites regulated by Hipk4. Moreover, Hipk4 and Rimbp3 deficiency mice display several common phenotypes, in particular with regard to the ectopic positioning of the manchette within spermatids, a presumed cause of sperm head deformities. Thus, Hipk4 might regulate manchette function through phosphorylation of Rimbp3, thereby playing essential role for sperm head formation and male fertility.

2022-08-02 | PXD019303 | Pride

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Project description:The spermatogenesis process is complex and delicate, and any error in any step may cause spermatogenesis arrested and even male infertility. Through mutation screening of patients with clinical azoospermia, we found a heterozygous site of the same mutation on CEP70. The centrosome protein 70 (Cep70) is involved in the regulation of microtubule assembly and shows a high expression trend during human spermatogenesis, but the specific mechanism of this protein in spermatogenesis is still unknown. Therefore, we deleted Cep70 in mice and founded that the deletion of Cep70 causes abnormal spermatogenesis and leads to male sterility. We found that knockout of Cep70 did not affect the prophase of meiosis I, but led to higher levels of thyroid hormone secretion, male germ cell apoptosis and abnormal spermiogenesis. By TEM and SEM analysis, we found that deletion of Cep70 results in abnormal formation of flagella and acrosome during spermiogenesis. TMT-labeled quantitative proteomic analysis revealed that the absence of Cep70 led to the significantly decrease of proteins associated with the formation of the flagella, head and acrosome of sperm and microtubule cytoskeleton according to the proteomic data. Taken together, our results show that Cep70 is essential for the acrosome biogenesis and flagella formation during spermiogenesis.

2021-09-10 | PXD023680 | Pride

Role of CEP112 and hnRNPA2B1 complex phase separation in RNA granule translation during spermiogenesis in humans and mice

Project description:Centrosomal proteins (CEPs) are active components of centrioles that mediate multiple biological processes, such as ciliogenesis and centriole biogenesis; therefore, CEP dysfunctions are broadly implicated in various human diseases. Although CEPs have been genetically linked to reproduction, the underlying molecular mechanisms remain poorly understood. Here, we report that knocking out Cep112 in mice causes male infertility with various sperm abnormalities and phenotypes consistent with human asthenoteratozoospermia. Microscopic observations revealed CEP112 is a novel component of atypical centrioles in human sperm cells. Mechanically, as an intrinsically disordered region-rich RNA-binding protein, CEP112 interacted with hnRNPA2B1 and condensed with key spermiogenesis-related mRNA molecules (Fsip2, Cfap61, and Cfap74) via liquid–liquid phase separation, which promoted RNA transport and the maintenance of local translation during spermiogenesis. Furthermore, two patients with bi-allelic variants in CEP112 were identified in a cohort of 568 unrelated infertile men, and in vitro experiments showed the mutations affected the phase-separation characteristics. Our findings provide new information on the roles of CEP112 and LLPS in male reproductive biology.

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Role of CEP112 and hnRNPA2B1 complex phase separation in RNA granule translation during spermiogenesis in humans and mice

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PHF7 Modulates BRDT Stability and Histone-to-Protamine Exchange during Spermiogenesis

Project description:Spermatogenesis is a complex process of sperm generation, including mitosis, meiosis, and spermiogenesis. During spermiogenesis, histones in post-meiotic spermatids are removed from chromatin and replaced by protamines. Although histone-to-protamine exchange is important for sperm nuclear condensation, the underlying regulatory mechanism is still poorly understood. Here, we identify PHD finger protein 7 (PHF7) as an E3 ubiquitin ligase for histone H3K14 in post-meiotic spermatids. Generation of Phf7-deficient mice and Phf7 C160A knockin mice with impaired E3 ubiquitin ligase activity reveals defects in histone-to-protamine exchange caused by dysregulation of histone removal factor Bromodomain, testis-specific (BRDT) in early condensing spermatids. Surprisingly, E3 ubiquitin ligase activity of PHF7 on histone ubiquitination leads to stabilization of BRDT by attenuating ubiquitination of BRDT. Collectively, our findings identify PHF7 as a critical factor for sperm chromatin condensation and contribute to mechanistic understanding of fundamental phenomenon of histone-to-protamine exchange and potential for drug development for the male reproduction system.

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