Sperm DNA methylation patterns at discrete CpGs and genes involved in embryonic development are related to bull fertility

Štiavnická, Miriama; Chaulot-Talmon, Aurélie; Perrier, Jean‐Philippe; Hošek, Petr; Kenny, David A.; Lonergan, Patrick; Kiefer, Hélène; Fair, Seán

doi:10.1186/s12864-022-08614-5

Cited by 16 publications

(17 citation statements)

References 110 publications

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“…These findings are in alignment with similar studies in humans and domesticated animals (Costes et al, 2022;Rotondo et al, 2021;Štiavnická et al, 2022;Sujit et al, 2020;Takeda et al, 2021), which have all highlighted the critical role of DNA methylation in the proper development and functioning of sperm cells. Candidate genes that we identified from gene networks built from DMclusters in sperm are well-studied and known to be involved in the regulation of developmental onset via epigenetic transcriptional repression in humans and mice, specifically in the multi-protein complexes formed by JARID2 and EZH2 in PRC2 (Fischer et al, 2022;Margueron & Reinberg, 2011;Pasini et al, 2010).…”

Section: Discussionsupporting

confidence: 90%

Epigenetic changes to gene pathways linked to male fertility in ex situ black‐footed ferrets

Tennenbaum,

Bortner,

Lynch

et al. 2024

Evolutionary Applications

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Environmental variation can influence the reproductive success of species managed under human care and in the wild, yet the mechanisms underlying this phenomenon remain largely mysterious. Molecular mechanisms such as epigenetic modifiers are important in mediating the timing and progression of reproduction in humans and model organisms, but few studies have linked epigenetic variation to reproductive fitness in wildlife. Here, we investigated epigenetic variation in black‐footed ferrets (Mustela nigripes), an endangered North American mammal reliant on ex situ management for survival and persistence in the wild. Despite similar levels of genetic diversity in human‐managed and wild‐born populations, individuals in ex situ facilities exhibit reproductive problems, such as poor sperm quality. Differences across these settings suggest that an environmentally driven decline in reproductive capacity may be occurring in this species. We examined the role of DNA methylation, one well‐studied epigenetic modifier, in this emergent condition. We leveraged blood, testes, and semen samples from male black‐footed ferrets bred in ex situ facilities and found tissue‐type specificity in DNA methylation across the genome, although 1360 Gene Ontology terms associated with male average litter size shared functions across tissues. We then constructed gene networks of differentially methylated genomic sites associated with three different reproductive phenotypes to explore the putative biological impact of variation in DNA methylation. Sperm gene networks associated with average litter size and sperm count were functionally enriched for candidate genes involved in reproduction, development, and its regulation through transcriptional repression. We propose that DNA methylation plays an important role in regulating these reproductive phenotypes, thereby impacting the fertility of male ex situ individuals. Our results provide information into how DNA methylation may function in the alteration of reproductive pathways and phenotypes in artificial environments. These findings provide early insights to conservation hurdles faced in the protection of this rare species.

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Section: Discussionsupporting

confidence: 90%

Epigenetic changes to gene pathways linked to male fertility in ex situ black‐footed ferrets

Tennenbaum,

Bortner,

Lynch

et al. 2024

Evolutionary Applications

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show abstract

“…Male fertility status-associated DNA methylation signatures in sperm can lead to altered transcriptomic profiles in bovine preimplantation embryos ( Kropp et al, 2017 ). Furthermore, we have recently reported, using the same population of HF and LF bulls as used in the current study, that sperm DNA methylation patterns at discrete CpGs and genes involved in embryonic development are related to bull fertility ( Stiavnicka et al, 2022 ).…”

Section: Discussionmentioning

confidence: 79%

Influence of sire fertility status on conceptus-induced transcriptomic response of the bovine endometrium

O’Callaghan

Sánchez

Rabaglino

et al. 2022

Front. Cell Dev. Biol.

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The aim was to examine the effect of sire fertility status on conceptus-induced changes in the bovine endometrial transcriptome. To generate elongated conceptuses, Day 7 blastocysts produced in vitro using frozen-thawed sperm from Holstein Friesian bulls (3 High fertility, HF and 3 Low fertility, LF) were transferred in groups of 5–10 into synchronized heifers (n = 7 heifers per bull) and recovered following slaughter on Day 15. Day 15 endometrial explants recovered from the uterine horn ipsilateral to the corpus luteum were recovered from synchronized cyclic heifers (n = 4). Explants from each heifer were co-cultured for 6 h in RPMI medium alone (Control) or with 100 ng/ml ovine recombinant interferon tau (IFNT) or with a single conceptus from each HF or LF bull. After 6 h, explants were snap frozen and stored at −80°C. Extracted mRNA was subjected to RNA-seq and the resulting data were analyzed with R software. The numbers of differentially expressed genes (DEG; FDR<0.05) were: HF vs. Control: 956; LF vs. Control: 1021; IFNT vs. Control: 1301; HF vs. LF: 2. Unsurprisingly, the majority of DEG (658) were common to all comparisons and were related to IFNT-induced changes in the endometrium. Prior to applying the adjusted p-value, there were 700 DEG between HF and LF, with 191 and 509 genes more expressed in HF or LF, respectively (p < 0.05). Overrepresentation analysis of KEGG pathways (FDR<0.05), revealed that DEG with higher expression in LF were involved in cell cycle and proteolysis, while those upregulated DEG by HF conceptuses were strongly associated with immune process pathways, such as TNF, NF-kappa B, cytokine-cytokine receptor interaction, and TLR signaling. These pathways were also enriched by DEG upregulated by IFNT compared to the Control. Furthermore, only the HF, and not the LF group, affected the expression of most genes in these pathways (p < 0.05) according to a negative binomial regression model. Finally, a weighted gene co-expression network analysis revealed two clusters of co-expressed genes associated with the HF conceptuses (p < 0.05), which were also enriched for the aforementioned pathways. In conclusion, HF conceptuses, similar to IFNT treatment, stimulated multiple pathways involved in immune response, which were apparently not affected by LF conceptuses.

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“…Male fertility status-associated DNA methylation signatures in sperm can lead to altered transcriptomic profiles in bovine preimplantation embryos (Kropp et al, 2017). Furthermore, we have recently reported, using the same population of HF and LF bulls as used in the current study, that sperm DNA methylation patterns at discrete CpGs and genes involved in embryonic development are related to bull fertility (Stiavnicka et al, 2022).…”

Section: Figurementioning

confidence: 75%

118 Influence of sire fertility status on conceptus-induced transcriptomic response of the bovine endometrium

O’Callaghan

Sánchez

Rabaglino

et al. 2021

Reprod. Fertil. Dev.

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The aim was to examine the effect of sire fertility status on conceptus-induced changes in the bovine endometrial transcriptome. To generate elongated conceptuses, Day 7 blastocysts produced in vitro using frozen-thawed sperm from Holstein Friesian bulls (3 High fertility, HF and 3 Low fertility, LF) were transferred in groups of 5-10 into synchronized heifers (n = 7 heifers per bull) and recovered following slaughter on Day 15. Day 15 endometrial explants recovered from the uterine horn ipsilateral to the corpus luteum were recovered from synchronized cyclic heifers (n = 4). Explants from each heifer were co-cultured for 6 h in RPMI medium alone (Control) or with 100 ng/ml ovine recombinant interferon tau (IFNT) or with a single conceptus from each HF or LF bull. After 6 h, explants were snap frozen and stored at −80 °C. Extracted mRNA was subjected to RNA-seq and the resulting data were analyzed with R software. The numbers of differentially expressed genes (DEG; FDR<0.05) were: HF vs. Control: 956; LF vs. Control: 1021; IFNT vs. Control: 1301; HF vs. LF: 2. Unsurprisingly, the majority of DEG (658) were common to all comparisons and were related to IFNT-induced changes in the endometrium. Prior to applying the adjusted p-value, there were 700 DEG between HF and LF, with 191 and 509 genes more expressed in HF or LF, respectively (p < 0.05). Overrepresentation analysis of KEGG pathways (FDR<0.05), revealed that DEG with higher expression in LF were involved in cell cycle and proteolysis, while those upregulated DEG by HF conceptuses were strongly associated with immune process pathways, such as TNF, NFkappa B, cytokine-cytokine receptor interaction, and TLR signaling. These pathways were also enriched by DEG upregulated by IFNT compared to the Control. Furthermore, only the HF, and not the LF group, affected the expression of most genes in these pathways (p < 0.05) according to a negative binomial regression model. Finally, a weighted gene co-expression network analysis revealed two clusters of co-expressed genes associated with the HF conceptuses (p < 0.05), which were also enriched for the aforementioned pathways. In conclusion, HF conceptuses, similar to IFNT

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Sperm DNA methylation patterns at discrete CpGs and genes involved in embryonic development are related to bull fertility

Cited by 16 publications

References 110 publications

Epigenetic changes to gene pathways linked to male fertility in ex situ black‐footed ferrets

Epigenetic changes to gene pathways linked to male fertility in ex situ black‐footed ferrets

Influence of sire fertility status on conceptus-induced transcriptomic response of the bovine endometrium

118 Influence of sire fertility status on conceptus-induced transcriptomic response of the bovine endometrium

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