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

ABSTRACT: 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. 4 samples

ORGANISM(S): Mus musculus

PROVIDER: GSE216936 | GEO | 2022/11/05

REPOSITORIES: GEO

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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.

2024-09-05 | PXD037982 | Pride

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Sub-centrosomal mapping identifies augmin-TuRC as part of a centriole-stabilizing scaffold

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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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2019-11-07 | GSE134825 | GEO

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

2019-11-07 | GSE134560 | GEO

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

2019-11-07 | GSE134521 | GEO

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