Transcriptome-wide N6-methyladenine methylation in granulosa cells of women with decreased ovarian reserve

Liu, Chang; Li, Linshuang; Yang, Bo; Zhao, Yiqing; Dong, Xiyuan; Zhu, Lixia; Ren, Xue; Huang, Bo; Yue, Jing; Jin, Lei; Zhang, Hanwang; Wang, Lan

doi:10.1186/s12864-022-08462-3

Cited by 9 publications

(6 citation statements)

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“…The finding that m 6 A modification of RNA is more frequent in oocytes than in liver cells at least in pigs has interesting implications for maternal transcripts, since it has been demonstrated that an abundance of m 6 A near the stop codon in 3’UTRs affects polyadenylation site selection [ 35 ]. Another study in pigs has detected a greater abundance of m 6 A marks in the 5’ and 3’ UTR gene coding regions [ 36 ]. Moreover, it has found that the m 6 A is abundant in granulosa cells and this mark is greater in small (< 3 mm) compared to large follicles (> 5 mm) demonstrating a potential role of m 6 A during folliculogenesis through the modulation of specific transcript [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Another study in pigs has detected a greater abundance of m 6 A marks in the 5’ and 3’ UTR gene coding regions [ 36 ]. Moreover, it has found that the m 6 A is abundant in granulosa cells and this mark is greater in small (< 3 mm) compared to large follicles (> 5 mm) demonstrating a potential role of m 6 A during folliculogenesis through the modulation of specific transcript [ 36 ]. Since reproductive organs like ovaries exhibits a rate of aging that is much faster than other somatic, it has also been shown that m 6 A associated gene in granulosa cells from aging women, an increased number of m 6 A methylated genes compared to younger female group [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Epitranscriptome marks detection and localization of RNA modifying proteins in mammalian ovarian follicles

et al. 2023

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Background Most of the resources that support the early development of the embryo are stored in the oocyte. Clearing of maternal resources and activation of the embryonic genome to produce its own mRNA transcripts marks the maternal-to-embryo transition. Dependence on stored mRNA can last from a few hours to several days, depending on animal species. The mechanisms regulating stabilization and recruitment of stored maternal transcripts have not yet been described in full detail but are known to involve reversible polyadenylation and modulation of 3’UTR-mediated elements. RNA epigenetic modifications, new players in this field, have an important role in RNA regulation and stabilization. Results The objectives of this study were first to determine if some of post-transcriptional methylation of stored mRNA is greater in oocytes than in somatic cells. We found that m6A, known to be the most prevalent and involved in various aspects of RNA metabolism and physiological functions, is particularly abundant in porcine oocyte mRNA compared to liver used as a somatic tissue reference. The second objective was to compare the epitranscriptome machinery, such as methyltransferases (“writers”), binding proteins (“readers”) and demethylases (“erasers”) catalyzing the different process, in follicles and oocytes of different mammalian species by immunofluorescence and confocal microscopy. The expression and localization patterns of these proteins differ between mice, pigs and cows ovaries and oocytes. m5C-associated proteins were generally less abundant. In contrast, m6A-associated proteins were expressed strongly during the early and late stages of folliculogenesis. Transzonal projections were found to contain more granules bearing the m5C mark in mice but both m5C and m6A methylation marks in association with mature oocytes of pigs and cows. Eraser proteins showed the greatest interspecies diversity in terms of distribution in the germinal tissues. Conclusions So far, few studies have looked at the oocyte and ovarian epitranscriptomic profile. Our findings indicate that a hitherto unrecognized species-specific layer of transcript regulation occurs at the RNA level and might be consequential during the oocyte transcriptional silencing period.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Epitranscriptome marks detection and localization of RNA modifying proteins in mammalian ovarian follicles

et al. 2023

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“…Moreover, it has found that the m 6 A is abundant in granulosa cells and this mark is greater in small (< 3 mm) compared to large follicles (> 5 mm) demonstrating a potential role of m 6 A during folliculogenesis through the modulation of speci c transcript [38]. Since reproductive organs like ovaries exhibits a rate of aging that is much faster than other somatic, it has also been shown that m 6 A associated gene in granulosa cells from aging women, an increased number of m 6 A methylated genes compared to younger female group [39]. Differences in polyadenylation patterns have been associated with differences in transcript stability, export, translation and localization [40].…”

Section: Discussionmentioning

confidence: 99%

Epitranscriptome marks detection and localization of RNA modifying proteins in mammalian ovarian follicles

Dubuc

Marchais

Gilbert

et al. 2022

Preprint

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Background Most of the resources that support the early development of the embryo are stored in the oocyte. Clearing of maternal resources and activation of the embryonic genome to produce its own mRNA transcripts marks the maternal-to-embryo transition. Dependence on stored mRNA can last from a few hours to several days, depending on animal species. The mechanisms regulating stabilization and recruitment of stored maternal transcripts have not yet been described in full detail but are known to involve reversible polyadenylation and modulation of 3’UTR-mediated elements. RNA epigenetic modifications, new players in this field, have an important role in RNA regulation and stabilization. Results The objectives of this study were first to determine if some of post-transcriptional methylation of stored mRNA is greater in oocytes than in somatic cells. We found that m6A, known to be the most prevalent and involved in various aspects of RNA metabolism and physiological functions, is particularly abundant in porcine oocyte mRNA compared to somatic tissues. The second objective was to compare the epitranscriptome machinery, such as methyltransferases (“writers”), binding proteins (“readers”) and demethylases (“erasers”) catalyzing the different process, in follicles and oocytes of different mammalian species by immunofluorescence and confocal microscopy. The expression and localization patterns of these proteins differ between mice, pigs and cows ovaries and oocytes. m5C-associated proteins were generally less abundant. In contrast, m6A-associated proteins were expressed strongly during the early and late stages of folliculogenesis. Transzonal projections were found to contain more granules bearing the m5C mark in mice but both m5C and m6A methylation marks in association with mature oocytes of pigs and cows. Eraser proteins showed the greatest interspecies diversity in terms of distribution in the germinal tissues. Conclusions So far, few studies have looked at the oocyte and ovarian epitranscriptomic profile. Our findings indicate that a hitherto unrecognized species-specific layer of transcript regulation occurs at the RNA level and might be consequential during the oocyte transcriptional silencing period.

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“…According to the instructions, total RNA from six testicular tissues was extracted using RNA-easyTM Isolation Reagent (R701-02, Vazyme, Nanjing, China), and the RNA samples were synthesized into cDNA using a Hifair® II 1st Strand cDNA Synthesis Kit (11121ES60, Yeasen, Shanghai, China). We performed qRT-PCR and analyzed gene expression as previously described [ 29 ]. The GAPDH gene was used as the endogenous reference.…”

Section: Methodsmentioning

confidence: 99%

Constructing a seventeen-gene signature model for non-obstructive azoospermia based on integrated transcriptome analyses and WGCNA

Chen

Yuan

et al. 2023

Reprod Biol Endocrinol

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Background Non-obstructive azoospermia (NOA) affects approximately 1% of the male population worldwide. The underlying mechanism and gene transcription remain unclear. This study aims to explore the potential pathogenesis for the detection and management of NOA. Methods Based on four microarray datasets from the Gene Expression Omnibus database, integrated analysis and weighted correlation network analysis (WGCNA) were used to obtain the intersected common differentially expressed genes (DESs). Differential signaling pathways were identified via GO and GSVA-KEGG analyses. We constructed a seventeen-gene signature model using least absolute shrinkage and selection operation (LASSO) regression, and validated its efficacy in another two GEO datasets. Three patients with NOA and three patients with obstructive azoospermia were recruited. The mRNA levels of seven key genes were measured in testicular samples, and the gene expression profile was evaluated in the Human Protein Atlas (HPA) database. Results In total, 388 upregulated and 795 downregulated common DEGs were identified between the NOA and control groups. ATPase activity, tubulin binding, microtubule binding, and metabolism- and immune-associated signaling pathways were significantly enriched. A seventeen-gene signature predictive model was constructed, and receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) values were 1.000 (training group), 0.901 (testing group), and 0.940 (validation set). The AUCs of seven key genes (REC8, CPS1, DHX57, RRS1, GSTA4, SI, and COX7B) were all > 0.8 in both the testing group and the validation set. The qRT-PCR results showed that consistent with the sequencing data, the mRNA levels of RRS1, GSTA4, and COX7B were upregulated, while CPS1, DHX57, and SI were downregulated in NOA. Four genes (CPS1, DHX57, RRS1, and SI) showed significant differences. Expression data from the HPA database showed the localization characteristics and trajectories of seven key genes in spermatogenic cells, Sertoli cells, and Leydig cells. Conclusions Our findings suggest a novel seventeen-gene signature model with a favorable predictive power, and identify seven key genes with potential as NOA-associated marker genes. Our study provides a new perspective for exploring the underlying pathological mechanism in male infertility.

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Transcriptome-wide N6-methyladenine methylation in granulosa cells of women with decreased ovarian reserve

Cited by 9 publications

References 88 publications

Epitranscriptome marks detection and localization of RNA modifying proteins in mammalian ovarian follicles

Epitranscriptome marks detection and localization of RNA modifying proteins in mammalian ovarian follicles

Epitranscriptome marks detection and localization of RNA modifying proteins in mammalian ovarian follicles

Constructing a seventeen-gene signature model for non-obstructive azoospermia based on integrated transcriptome analyses and WGCNA

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