Kristina W Olsen1, Juan Castillo-Fernandez2, Andrew Cho Chan3, Nina la Cour Freiesleben4, Anne Zedeler5, Mona Bungum6, Alexia Cardona7, John R B Perry8, Sven O Skouby9, Eva R Hoffmann3, Gavin Kelsey10, Marie Louise Grøndahl9. 1. Department of Obstetrics and Gynaecology, Department of Reproductive Medicine, Hospital Herlev, Copenhagen University, Copenhagen, Denmark; DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: kristina.wendelboe.olsen@regionh.dk. 2. Epigenetics Programme, Babraham Institute, Cambridge, United Kingdom. 3. DNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Department of Obstetrics and Gynaecology, The Fertility Clinic, Hospital Hvidovre, Copenhagen University, Copenhagen, Denmark; VivaNeo Fertility Clinics, Stork IVF Clinic A/S, Copenhagen, Denmark. 5. Department of Obstetrics and Gynaecology, The Fertility Clinic, Hospital Hvidovre, Copenhagen University, Copenhagen, Denmark. 6. Reproductive Medicine Centre, Skåne University Hospital, Malmoe, Sweden. 7. Medical Research Council Epidemiology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, Cambridge, United Kingdom; Department of Genetics, University of Cambridge, Cambridge, United Kingdom. 8. Medical Research Council Epidemiology Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, Cambridge, United Kingdom. 9. Department of Obstetrics and Gynaecology, Department of Reproductive Medicine, Hospital Herlev, Copenhagen University, Copenhagen, Denmark. 10. Epigenetics Programme, Babraham Institute, Cambridge, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
Abstract
OBJECTIVE: To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve. DESIGN: Prospectively collected material from a multicenter cohort of women undergoing fertility treatment. SETTING: Private and university-based facilities for clinical services and research. PATIENT(S): One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations. RESULT(S): Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485). CONCLUSION(S): The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.
OBJECTIVE: To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve. DESIGN: Prospectively collected material from a multicenter cohort of women undergoing fertility treatment. SETTING: Private and university-based facilities for clinical services and research. PATIENT(S): One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations. RESULT(S): Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485). CONCLUSION(S): The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.
Authors: Mette W Christensen; David L Keefe; Fang Wang; Christine S Hansen; Isaac J Chamani; Carolyn Sommer; Mette Nyegaard; Palle D Rohde; Anders L Nielsen; Jonas Bybjerg-Grauholm; Ulrik S Kesmodel; Ulla B Knudsen; Kirstine Kirkegaard; Hans Jakob Ingerslev Journal: J Assist Reprod Genet Date: 2021-10-01 Impact factor: 3.412
Authors: Yunsung Lee; Jon Bohlin; Christian M Page; Haakon E Nustad; Jennifer R Harris; Per Magnus; Astanand Jugessur; Maria C Magnus; Siri E Håberg; Hans I Hanevik Journal: Hum Reprod Date: 2022-08-25 Impact factor: 6.353