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Setd2-dependent H3K36me3 is required for Acrbp1 and protamine transcriptions and spermiogenesis in mice

ABSTRACT: Spermatogenesis is precisely cotrolled by complex gene expression programs and involves epigenetic reprogramming including histone modification and DNA methylation. Setd2 catalyzes the trimethylation of histone H3 Lys36 (H3K36me3) and plays key roles in embryonic stem cell differentiation and somatic cell development; however, its role in male germ cell development remains elusive. Here we demonstrate an essential role of Setd2 for spermiogenesis. We show that targeted knockout of Setd2 in germ cells causes aberrant spermiogenesis with acrosomal malformation before step 8 round spermatid stage, resulting in complete male infertile. Furthermore, we show a complete loss of H3K36me3 and a significant altered gene expression profile, including Acrbp1 and protamines, caused by Setd2 deficiency. Our findings reveal a previously underappreciated role of Setd2-dependent H3K36me3 for spermiogenesis and improved the understanding of epigenetic disorders underlying male infertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE108717 | GEO | 2018/04/28

REPOSITORIES: GEO

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Setd2-dependent H3K36me3 is required for Acrbp1 and protamine transcriptions and spermiogenesis in mice

Project description:Setd2-dependent H3K36me3 is required for Acrbp1 and protamine transcriptions and spermiogenesis in mice

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The deubiquitinase cofactor UAF1 interacts with USP1 and plays an essential role in spermiogenesis

Project description:Spermiogenesis defines the final phase of male germ cell differentiation. Multiple deubiquitinating enzymes have been linked to spermiogenesis, yet the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis and male fertility. We selectively deleted Uaf1 in premeiotic germ cells using Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. We found that UAF1 interacts and colocalizes with USP1 in testes. Conditional knockout of Uaf1 in testes results in disturbed expression and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. We used tandem mass tag-based proteomics to identify differentially expressed proteins and potential underlying mechanisms, and found that conditional knockout Uaf1 in testes results in reduced levels of proteins essential for spermiogenesis. Thus, the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.

2024-02-07 | PXD046120 | Pride

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.

2020-07-28 | GSE136752 | GEO

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.

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

Loss of Cep70 function affects acrosome biogenesis and flagella formation during spermiogenesis

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

EWSR1 is critical for post-meiotic transcription and spermiogenesis

Project description:Spermatogenesis is precisely controlled by complex gene expression programs. During mammalian male germ cell development, a crucial feature is the repression of transcription before spermatid elongation. Previously, we discovered that RNA-binding protein EWSR1 plays an important role in meiotic recombination and is highly expressed in late meiotic cells and post-meiotic cells. Here, we used a Ewsr1 pachytene stage-specific knockout mouse model to study its roles at late meiotic prophase I and in spermatozoa maturation. We show that loss of EWSR1 at this stage does not affect proper meiosis completion, but the developing germ cells exhibit defects in spermatid elongation and chromocenter formation. In the Ewsr1 conditional knockout testes, expression of many genes regulating spermatid differentiation is impaired, suggesting that EWSR1 may play important role in regulation of spermiogenesis related mRNA synthesis and spermatid differentiation.

2021-06-01 | GSE120989 | GEO

Male mammalian meiosis and spermiogenesis is critically dependent on the shared functions of the katanin proteins KATNA1 and KATNAL1

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2023-10-30 | PXD038404 | Pride

Spermiogenesis alterations in the absence of CTCF revealed by single cell RNA sequencing

Project description:In this work, we performed single cell RNA sequencing in spermatogenic cells without CTCF. We uncovered defects in transcriptional programs that explain the severity of the damage in the produced sperm. At early stages of spermatogenesis, transcriptional alterations are mild. As germ cells go throughout the specialization stage or spermiogenesis, transcriptional profiles become more altered. We found spermatid defects that support the alterations in the transcriptional profiles, and thus we conclude that CTCF depletion alters several transcriptional profiles mostly during spermiogenesis. Our data highlights the importance of CTCF at the different stages of spermatogenesis.

2023-02-17 | GSE166774 | GEO

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