Epimutations in the male germ cell and possible consequences for ART outcome
Final Report Abstract
The causes and consequences of epimutations in the sperm of infertile men have been thoroughly scrutinized in the recent years. This project took different approaches, based on innovative techniques for DNA methylation analysis, to characterize the DNA methylation defects occurring in the male germline as well explore the diagnostic and prognostic value of these measurements, with a translational outlook. The work and collaboration developed between the groups of Münster and Würzburg not only achieved the main objectives set at the beginning of this project, but also originated new hypothesis concerning the impact of epimutations in human reproduction as well as regarding the origin of these epimutations in the male germline. Through the work developed by the Münster group, it was possible to ensure the epigenetic safety of cryopreserved sperm samples. Moreover, a reference range for a commonly analysed imprinted gene, MEST, was determined and can be used in clinical practice for the diagnosis of men with idiopathic infertility. The effects of two epigenetic drugs, decitabine and vorinostat, to male fertility, epigenetic programming of the male germline, and their potential transgenerational effects was analysed. It could be demonstrated that, although both drugs caused direct effects, these were not severe and no transgenerational epigenetic effects could be found. The use of DNA methylation assays by the Würzburg group revealed the widespread epigenetic variations that occur in the genome the sperm of infertile men, at the DNA methylation level. Moreover, it provided new candidate genes associated with human male subinfertility/infertility. Both the Münster and the Würzburg then used the same method of DBS (Roche 454/GS Junior) but different approaches at sample selection and data analysis to evaluate the occurrence of epigenetic heterogeneity in sperm. Both groups have reached the same conclusion that sperm of infertile or subfertile men display higher levels of epigenetic heterogeneity at the DNA methylation level. Moreover, it was be concluded that the abnormal methylation levels found in the sperm of infertile men by numerous studies are probably due to the existence of different populations of sperm with different epigenetic programming, likely due to epimutations occurring in percursor cells such as primordial germ cells.
Publications
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(2012) Routine cryopreservation of spermatozoa is safe - evidence from the DNA methylation pattern of nine spermatozoa genes. Journal of Assisted Reproduction and Genetics 29:943-950
Kläver R, Bleiziffer A, Redmann K, Mallidis C, Kliesch S, Gromoll J
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(2013) Broad DNA methylation changes of spermatogenesis, inflammation and immune response related genes in a subgroup of sperm samples for assisted reproduction. Andrology 1:822-829
Schütte B, El Hajj N, Kuhtz J, Nanda I, Gromoll J, Hahn T, Dittrich M, Schorsch M, Müller T, Haaf T
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(2013) DNA methylation in spermatozoa as a prospective marker in andrology. Andrology 1:731-740
Kläver R, Tüttelmann F, Bleiziffer A, Haaf T, Kliesch S, Gromoll J
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(2014) Bringing epigenetics into the diagnostics of the andrology laboratory: challenges and perspectives. Asian Journal of Andrology 16:669-674
Kläver R, Gromoll J
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(2014) Epigenetic heterogeneity of developmentally important genes in human sperm: implications for assisted reproduction outcome. Epigenetics 9:1648-1658
Kuhtz J, Schneider E, El Hajj N, Zimmermann L, Fust O, Linek B, Seufert R, Hahn T, Schorsch M, Haaf T
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(2015) Direct but no transgenerational effects of decitabine and vorinostat on male fertility. PLoS One 10:e0117839
Kläver R, Sánchez V, Damm OS, Redmann K, Lahrmann E, Sandhowe-Klaverkamp R, Rohde C, Wistuba J, Ehmcke J, Schlatt S, Gromoll J
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(2015) Epigenetic germline mosaicism in infertile men. Human Molecular Genetics 24:1295-1304
Laurentino S, Beygo J, Nordhoff V, Kliesch S, Wistuba J, Borgmann J, Buiting K, Horsthemke B, Gromoll J
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(2016) On the origin of sperm epigenetic heterogeneity. Reproduction 151:R71-8
Laurentino SS, Borgmann J, Gromoll J
