Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

A distinctive epigenetic ageing profile in human granulosa cells

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Fetal fraction of cell-free DNA in pregnancies after fresh or frozen embryo transfer following assisted reproductive technologies

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Corrigendum. Birth weight for gestational age and the risk of infertility: a Danish cohort study

    Research output: Contribution to journalJournal articleResearch

  3. Type 1 diabetes in children born after assisted reproductive technology: a register-based national cohort study

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Birth weight for gestational age and the risk of infertility: a Danish cohort study

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Endometrial scratch injury with office hysteroscopy before IVF/ICSI: A randomised controlled trial

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Tumor miRNA expression profile is related to vestibular schwannoma growth rate

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Review of injection techniques for spermatogonial stem cell transplantation

    Research output: Contribution to journalReviewResearchpeer-review

  4. Effect of dosage of 17ß-estradiol on uterine growth in Turner syndrome - a randomized controlled clinical pilot trial

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

STUDY QUESTION: Does women's age affect the DNA methylation (DNAm) profile differently in mural granulosa cells (MGCs) from other somatic cells?

SUMMARY ANSWER: Accumulation of epimutations by age and a higher number of age-related differentially methylated regions (DMR) in MGCs were found compared to leukocytes from the same woman, suggesting that the MGCs have a distinctive epigenetic profile.

WHAT IS KNOWN ALREADY: The mechanisms underlying the decline in women's fertility from the mid-30s remain to be fully elucidated. The DNAm age of many healthy tissues changes predictably with and follows chronological age, but DNAm age in some reproductive tissues has been shown to depart from chronological age (older: endometrium; younger: cumulus cells, spermatozoa).

STUDY DESIGN, SIZE, DURATION: This study is a multicenter cohort study based on retrospective analysis of prospectively collected data and material derived from healthy women undergoing IVF or ICSI treatment following ovarian stimulation with antagonist protocol. One hundred and nineteen women were included from September 2016 to June 2018 from four clinics in Denmark and Sweden.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were obtained from 118 healthy women with varying ovarian reserve status. MGCs were collected from 63 of the 119 women by isolation from pooled follicles immediately after oocyte retrieval. DNA from leukocytes and MGCs was extracted and analysed with a genome-wide methylation array. Data from the methylation array were processed using the ENmix package. Subsequently, DNAm age was calculated using established and tailored age predictors and DMRs were analysed with the DMRcate package.

MAIN RESULTS AND ROLE OF CHANCE: Using established age predictors, DNAm age in MGCs was found to be considerable younger and constant (average: 2.7 years) compared to chronological age (average: 33.9 years). A Granulosa Cell clock able to predict the age of both MGCs (average: 32.4 years) and leukocytes (average: 38.8 years) was successfully developed. MGCs differed from leukocytes in having a higher number of epimutations (P = 0.003) but predicted telomere lengths unaffected by age (Pearson's correlation coefficient = -0.1, P = 0.47). DMRs associated with age (age-DMRs) were identified in MGCs (n = 335) and in leukocytes (n = 1) with a significant enrichment in MGCs for genes involved in RNA processing (45 genes, P = 3.96 × 10-08) and gene expression (152 genes, P = 2.3 × 10-06). The top age-DMRs included the metastable epiallele VTRNA2-1, the DNAm regulator ZFP57 and the anti-Müllerian hormone (AMH) gene. The apparent discordance between different epigenetic measures of age in MGCs suggests that they reflect difference stages in the MGC life cycle.

LARGE SCALE DATA: N/A.

LIMITATIONS, REASONS FOR CAUTION: No gene expression data were available to associate with the epigenetic findings. The MGCs are collected during ovarian stimulation, which may influence DNAm; however, no correlation between FSH dose and number of epimutations was found.

WIDER IMPLICATIONS OF THE FINDINGS: Our findings underline that the somatic compartment of the follicle follows a different methylation trajectory with age than other somatic cells. The higher number of epimutations and age-DMRs in MGCs suggest that their function is affected by age.

STUDY FUNDING/COMPETING INTEREST(S): This project is part of ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS, the Danish National Research Foundation and the European Research Council. The authors declare no conflict of interest.

Original languageEnglish
JournalHuman reproduction (Oxford, England)
Volume35
Issue number6
Pages (from-to)1332-1345
Number of pages14
ISSN0268-1161
DOIs
Publication statusPublished - 1 Jun 2020

ID: 59972844