SirT1 is required in the male germ cell for differentiation and fecundity in mice

Bell, Eric L.; Nagamori, Ippei; Williams, Eric O.; Rosario, Amanda M. Del; Bryson, Bryan; Watson, Nicki; White, Forest M.; Sassone–Corsi, Paolo; Guarente, Leonard

doi:10.1242/dev.110627

Cited by 88 publications

(94 citation statements)

References 35 publications

(48 reference statements)

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“…In the testis of Sirt1 F/F ; Tnap-Cre mice, we observed many TUNEL signals in the germ cells (Fig. S3), which was consistent with the findings of some previous studies (Bell et al, 2014;Kolthur-Seetharam et al, 2009). In yeast, Sir2 can inhibit ribosomal DNA recombination and relocalize to the sites of DNA breaks; the absence of Sir2 activity leads to silencing defects, sensitivity to DNA damage and increased genomic instability (Denu, 2003;Guarente and Picard, 2005).…”

Section: Discussionsupporting

confidence: 91%

“…Bell et al (2014) found that the histone to protamine transition was disrupted in Sirt1-deficient spermatids, and this might partially account for the decrease in sperm count. An alternative explanation relates to the functional diversity of Sirt1 during spermatogenesis.…”

Section: Discussionmentioning

confidence: 98%

“…It has been proposed that Sirt1 might regulate spermatogenesis at postnatal stages by controlling hypothalamus-pituitary gonadotropin (HPG) signalling (KolthurSeetharam et al, 2009). A detailed analysis of the functions of Sirt1 in the germ line of Sirt1 −/− mice (Coussens et al, 2008) and meiotic-specific Sirt1 knockout mice revealed that Sirt1 might be involved in the differentiation of spermatogenic stem cells and the transition from histone to protamine (Bell et al, 2014). In addition, the researchers found an increased proportion of abnormal spermatozoa in the Sirt1-deficient mice; however, the mechanism by which Sirt1 deficiency in germ cells leads to malformed spermatozoa and the identity of its specific substrate during spermiogenesis remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice

Liu¹,

Song²,

Wang³

et al. 2017

Journal of Cell Science

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Sirt1 is a member of the sirtuin family of proteins and has important roles in numerous biological processes. Sirt1 −/− mice display an increased frequency of abnormal spermatozoa, but the mechanism of Sirt1 in spermiogenesis remains largely unknown. Here, we report that Sirt1 might be directly involved in spermiogenesis in germ cells but not in steroidogenic cells. Germ cell-specific Sirt1 knockout mice were almost completely infertile; the early mitotic and meiotic progression of germ cells in spermatogenesis were not obviously affected after Sirt1 depletion, but subsequent spermiogenesis was disrupted by a defect in acrosome biogenesis, which resulted in a phenotype similar to that observed in human globozoospermia. In addition, LC3 and Atg7 deacetylation was disrupted in spermatids after knocking out Sirt1, which affected the redistribution of LC3 from the nucleus to the cytoplasm and the activation of autophagy. Furthermore, Sirt1 depletion resulted in the failure of LC3 to be recruited to Golgi apparatus-derived vesicles and in the failure of GOPC and PICK1 to be recruited to nucleus-associated acrosomal vesicles. Taken together, these findings reveal that Sirt1 has a novel physiological function in acrosome biogenesis.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice

Liu¹,

Song²,

Wang³

et al. 2017

Journal of Cell Science

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“…Most of the core nucleosomal histones are displaced from the chromatin during steps 9-12 of spermiogenesis in the mouse, and condensed spermatids or sperm retain only small residual amounts of histones H3 and H4 (Li et al, 2014;Meistrich et al, 2003). Increased retention of histone H3 and H4 in spermatids/sperm has been closely linked to male infertility in many gene-KO mouse models (Bell et al, 2014;Li et al, 2014;Lu et al, 2010;Zhuang et al, 2014). Prm2 is synthesized as a precursor protein that binds to the chromatin and then undergoes proteolytic processing giving rise to several intermediates and finally mature Prm2 (Balhorn, 2007;Wu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

TSSK6 is required for γH2AX formation and the histone-to-protamine transition during spermiogenesis

Jha

Tripurani

Johnson

2017

Journal of Cell Science

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Spermiogenesis includes transcriptional silencing, chromatin condensation and extensive morphological changes as spermatids transform into sperm. Chromatin condensation involves histone hyperacetylation, transitory DNA breaks, histone H2AX (also known as H2AFX) phosphorylation at Ser139 (γH2AX), and replacement of histones by protamines. Previously, we have reported that the spermatid protein kinase TSSK6 is essential for fertility in mice, but its specific role in spermiogenesis is unknown. Here, we show that TSSK6 expression is spatiotemporally coincident with γH2AX formation in the nuclei of developing mouse spermatids. RNAsequencing analysis demonstrates that genetic ablation of Tssk6 does not impact gene expression or silencing in spermatids. However, loss of TSSK6 blocks γH2AX formation, even though the timing and level of the transient DNA breaks is unaltered. Further, Tssk6-knockout sperm contained increased levels of histones H3 and H4, and protamine 2 precursor and intermediate(s) indicative of a defective histone-to-protamine transition. These results demonstrate that TSSK6 is required for γH2AX formation during spermiogenesis, and also link γH2AX to the histone-to-protamine transition and male fertility.

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“…Several of the histone-modifying enzymes that are upregulated in mouse early meiotic cells ( Fig. 1; see Data Set S1 in the supplemental material) are essential for development, as their deletion in the mouse leads to prenatal or postnatal lethality, defects in spermatogenesis, chromosomal aberrations, and/or infertility (e.g., the deletion of Hat1, Suv39h1/2, Suv4-20h1/2, Mll1, Prdm9, Sirt1, or Sirt6) (39)(40)(41)(65)(66)(67)(68)(69)(70). Further, some of the histone acetylation and methylation marks that are deposited by these HATs and HMTs have defined roles in mammalian germ cell development and meiosis.…”

Section: Discussionmentioning

confidence: 99%

Functional Roles of Acetylated Histone Marks at Mouse Meiotic Recombination Hot Spots

Getun

Fallahi

et al. 2017

Molecular and Cellular Biology

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Meiotic recombination initiates following the formation of DNA doublestrand breaks (DSBs) by the Spo11 endonuclease early in prophase I, at discrete regions in the genome coined "hot spots." In mammals, meiotic DSB site selection is directed in part by sequence-specific binding of PRDM9, a polymorphic histone H3 (H3K4Me3) methyltransferase. However, other chromatin features needed for meiotic hot spot specification are largely unknown. Here we show that the recombinogenic cores of active hot spots in mice harbor several histone H3 and H4 acetylation and methylation marks that are typical of open, active chromatin. Further, deposition of these open chromatin-associated histone marks is dynamic and is manifest at spermatogonia and/or pre-leptotene-stage cells, which facilitates PRDM9 binding and access for Spo11 to direct the formation of DSBs, which are initiated at the leptotene stage. Importantly, manipulating histone acetylase and deacetylase activities established that histone acetylation marks are necessary for both hot spot activity and crossover resolution. We conclude that there are functional roles for histone acetylation marks at mammalian meiotic recombination hot spots.KEYWORDS crossover, double-strand break initiation, histone acetylation, meiotic recombination, mouse meiosis M eiotic recombination commences only following the double-stranded cleavage of DNA by the meiosis-specific Spo11 endonuclease in leptotene to early zygotene meiosis I cells (1-4), at discrete regions of the genome coined meiotic recombination "hot spots" (5, 6). Meiotic DNA double-strand breaks (DSBs) are then repaired by homologous recombination (HR) pathways, mediated by the meiosis-specific Rad51 and DMC1 repair proteins in mid-and late-zygotene-stage cells (4,7,8). The chromatin features, regulatory factors, and histone modifications that contribute to the control of mammalian meiotic DSB site selection by Spo11 and to the initiation, crossover (CO) activity, and resolution of meiotic recombination events are generally poorly understood.In mice and humans, one key regulator of DSB site selection is PRDM9 (5, 9-13), a polymorphic histone H3 methyltransferase that binds in a sequence-specific fashion to polymorphic sequences that are present in nearly 90% of hot spot cores (14) and that generates the trimethylated histone H3 lysine 4 (H3K4Me3) mark that is a hallmark of open chromatin (15,16). However, in addition to the known role for the H3K4Me3 mark at hot spot cores, an emerging body of evidence suggests that several histone modifications associated with open chromatin, including acetylation, methylation, and

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SirT1 is required in the male germ cell for differentiation and fecundity in mice

Cited by 88 publications

References 35 publications

Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice

Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice

TSSK6 is required for γH2AX formation and the histone-to-protamine transition during spermiogenesis

Functional Roles of Acetylated Histone Marks at Mouse Meiotic Recombination Hot Spots

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