Epigenetic profiling of mouse uteri across reproductive aging
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PROVIDER: PRJNA1271427 | ENA |
REPOSITORIES: ENA
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Project description:Advanced maternal age increases the risk of pregnancy complications because of a higher incidence of karyotypic imbalances in the oocyte. A very important yet much less explored contribution to this risk, however, is the declining capacity of the uterus to adapt to the hormonal stimulus of pregnancy. As such, it has remained unknown what drives the uterine aging phenotype on the molecular and cellular level. Here, we show in mice that maternal aging is associated with a progressive increase in transcriptional variation that is accompanied by a drastic accumulation of activating histone marks. Importantly, the transcriptional signatures associated with uterine aging differ substantially from those of organismal aging. Single-cell deconvolution analysis demonstrates that maternal age-induced effects originate in the epithelial compartment and specifically entail a dramatic up-regulation of the pioneer transcription factor FOXC1, linked to an accumulation of H3K4me3 and H3K27ac across the locus. FOXC1 over-expression in human endometrial cells causes profound transcriptomic shifts and increases proliferation rates, recapitulating the aging phenotype. Using endometrial epithelial organoids of young and aged mice, we find that aging hallmarks including Foxc1 up-regulation and H3K27ac hyper-enrichment are conserved in vitro. In line with the epithelial hyperplasia phenotype seen in vivo, endometrial epithelial organoids from aged mice are larger and mis-express key factors critical for uterine gland maturity and function, most notably SOX9. Collectively, our data highlight the specific susceptibility of uterine epithelial cells to early-onset aging, with early changes manifesting in an increase in activating epigenetic marks that coalesce on the mis-regulation of FOXC1.
2025-08-11 | GSE298816 | GEO
Project description:In vitro fertilization (IVF) is an assisted reproductive technology that has enabled millions of births. Although considered safe, emerging evidence suggests that IVF may have long-term health adverse outcomes in offspring, though its impact on female reproduction, especially on reproductive aging is largely unknown. Here, we use a mouse model to investigate how IVF influences female reproductive and transgenerational health outcomes. We assessed IVF-conceived fetal (E18.5) and adult (12-week and 39-week) female offspring, identifying alterations in ovarian-to-body weight ratios, ovarian morphology, serum sex hormone levels, and transcriptomic and DNA methylation profiles in ovaries, oocytes, and cumulus cells, consistent with biomarkers of accelerated reproductive aging. The offspring of IVF females and wild-type males exhibited altered fetal-to-placental weight ratios, placental morphology, and dysregulated placental gene expression. At 12-weeks-of-age, offspring showed increased body weight, disrupted lipid and glucose metabolism, and transcriptomic and epigenetic changes in liver and reproductive organs. Our results highlight the need for deeper mechanistic understanding of assisted reproduction’s long-term and multigenerational impacts on female reproductive health.
2026-01-29 | GSE307881 | GEO
Project description:Reproductive aging occurs earlier than systemic aging as a woman’s ovarian reserve is depleted as she approaches menopause. There is considerable variability around when a woman reaches menopause, yet few contributing factors have been identified. Assessment of reproductive age involves measuring a woman’s ovarian reserve and oocyte function, which has clearly-defined parameters in in vitro fertilization. As ovarian reserve declines, Anti-Mullerian hormone levels fall and women produce fewer oocytes after ovarian stimulation. Oocyte function also declines, as fewer mature oocytes are produced and have the capacity to be fertilized. The mechanisms of these age-related declines are unclear, but may involve changes in DNA methylation, which are known to occur with age and may reflect the biological processes underlying reproductive aging. We hypothesize that DNA methylation patterns will be associated with ovarian reserve and oocyte function, and that women with poor ovarian reserve and oocyte function will experience epigenetic age acceleration and will accumulate more stochastic epigenetic mutations. To test this hypothesis, we will first perform an epigenome-wide association to examine DNA methylation patterns associated with each measure of ovarian reserve and oocyte function. Then, we will calculate epigenetic age and age acceleration, which are indicators of biological aging, and stochastic epigenetic mutations, which increase with age and may disrupt key biological pathways in an individual.
2026-03-27 | GSE293125 | GEO
Project description:In Vitro Fertilization Induces Premature Reproductive Aging and Multigenerational Epigenetic Changes in Female Mouse Offspring
| PRJNA1327674 | ENA
Project description:The testis, efferent ductules, epididymis, and vas deferens, constituting the majority of male reproductive tract, are the regions for testosterone production, spermatogenesis, and sperm maturation, storage and discharge, but whether these regions change during aging is unknown. Here, we addressed this by investigating the adult (3-month) and aged (18-month) transcriptomes from seven regions of male mouse reproductive tract：the testis, efferent ductules, initial segment, caput, corpus and cauda epididymis, and vas deferens. We identified various of region-specific genes across different regions of male mouse reproductive tract. Moreover, we identified region-dependent changes of transcripts at an anatomic resolution. This study provides a framework for futher studies on male reproducitve aging.
2022-03-02 | GSE181426 | GEO
Project description:Epigenetic Biomarkers of Aging
| PRJNA875201 | ENA
Project description:Epigenetic Biomarkers of Aging
| PRJNA875202 | ENA
Project description:Reproductive aging is an increasing health concern affecting family planning and overall well-being. While extensively studied in females, the mechanisms driving male reproductive aging remain largely unexamined. Here we found that mammalian Sirtuin 7 (SIRT7) sustains spermatogenesis in an age-dependent manner through the control of histone 3 lysine 36 acetylation (H3K36ac). SIRT7 deficiency in mice resulted in increased levels of H3K36ac in spermatogonia and spermatocytes, a pattern also observed during natural testicular aging. SIRT7 deficiency altered chromatin accessibility, which was directly linked to H3K36ac activity in a germ cell line, and increased vulnerability to genotoxic stress. Importantly, undifferentiated spermatogonia, which are required for continuous sperm production, decreased prematurely in Sirt7-/- mice and showed enhanced genome damage accumulation during aging or under acute environmental stress. These changes were concurrent with age-dependent defects in double strand break (DBS) repair and partial meiotic arrest. Taken together, our results indicate that SIRT7 connects H3K36ac epigenetic regulation to long-term genome stability in male germ cells, ensuring steady-state spermatogenesis during the lengthy male reproductive lifespan.
2026-03-31 | GSE314213 | GEO
Project description:DNA methylation differences underlying female reproductive aging
| PRJNA1242855 | ENA
Project description:Reproductive aging is an increasing health concern affecting family planning and overall well-being. While extensively studied in females, the mechanisms driving male reproductive aging remain largely unexamined. Here we found that mammalian Sirtuin 7 (SIRT7) sustains spermatogenesis in an age-dependent manner through the control of histone 3 lysine 36 acetylation (H3K36ac). SIRT7 deficiency in mice resulted in increased levels of H3K36ac in spermatogonia and spermatocytes, a pattern also observed during natural testicular aging. SIRT7 deficiency altered chromatin accessibility, which was directly linked to H3K36ac activity in a germ cell line, and increased vulnerability to genotoxic stress. Importantly, undifferentiated spermatogonia, which are required for continuous sperm production, decreased prematurely in Sirt7-/- mice and showed enhanced genome damage accumulation during aging or under acute environmental stress. These changes were concurrent with age-dependent defects in double strand break (DBS) repair and partial meiotic arrest. Taken together, our results indicate that SIRT7 connects H3K36ac epigenetic regulation to long-term genome stability in male germ cells, ensuring steady-state spermatogenesis during the lengthy male reproductive lifespan.
2026-03-31 | GSE314480 | GEO