@article{KuhtzSchneiderElHajjetal.2014,
  author    = {Kuhtz, Juliane and Schneider, Eberhard and El Hajj, Nady and Zimmermann, Lena and Fust, Olga and Linek, Bartosz and Seufert, Rudolf and Hahn, Thomas and Schorsch, Martin and Haaf, Thomas},
  title     = {Epigenetic heterogeneity of developmentally important genes in human sperm: Implications for assisted reproduction outcome},
  series = {Epigenetics},
  volume    = {9},
  journal   = {Epigenetics},
  number    = {12},
  doi       = {10.4161/15592294.2014.988063},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150261},
  pages     = {1648-1658},
  year      = {2014},
  abstract  = {The molecular basis of male infertility is poorly understood, the majority of cases remaining unsolved. The association of aberrant sperm DNA methylation patterns and compromised semen parameters suggests that disturbances in male germline epigenetic reprogramming contribute to this problem. So far there are only few data on the epigenetic heterogeneity of sperm within a given sample and how to select the best sperm for successful infertility treatment. Limiting dilution bisulfite sequencing of small pools of sperm from fertile donors did not reveal significant differences in the occurrence of abnormal methylation imprints between sperm with and without morphological abnormalities. Intracytoplasmic morphologically selected sperm injection was not associated with an improved epigenetic quality, compared to standard intracytoplasmatic sperm injection. Deep bisulfite sequencing (DBS) of 2 imprinted and 2 pluripotency genes in sperm from men attending a fertility center showed that in both samples with normozoospermia and oligoasthenoteratozoospermia (OAT) the vast majority of sperm alleles was normally (de)methylated and the percentage of epimutations (allele methylation errors) was generally low (<1\%). However, DBS allowed one to identify and quantify these rare epimutations with high accuracy. Sperm samples not leading to a pregnancy, in particular in the OAT group, had significantly more epimutations in the paternally methylated GTL2 gene than samples leading to a live birth. All 13 normozoospermic and 13 OAT samples leading to a child had <1\% GTL2 epimutations, whereas one (7\%) of 14 normozoospermic and 7 (50\%) of 14 OAT samples without pregnancy displayed 1-14\% GTL2 epimutations.},
  language  = {en}
}
@article{SchneiderPliushchElHajjetal.2010,
  author    = {Schneider, Eberhard and Pliushch, Galyna and El Hajj, Nady and Galetzka, Danuta and Puhl, Alexander and Schorsch, Martin and Frauenknecht, Katrin and Riepert, Thomas and Tresch, Achim and Mueller, Annette M. and Coerdt, Wiltrud and Zechner, Ulrich and Haaf, Thomas},
  title     = {Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68371},
  year      = {2010},
  abstract  = {DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of genespecific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism.},
  subject      = {Medizin},
  language  = {en}
}
@article{HaertleMaierhoferBoecketal.2017,
  author    = {Haertle, Larissa and Maierhofer, Anna and B{\"o}ck, Julia and Lehnen, Harald and B{\"o}ttcher, Yvonne and Bl{\"u}her, Matthias and Schorsch, Martin and Potabattula, Ramya and El Hajj, Nady and Appenzeller, Silke and Haaf, Thomas},
  title     = {Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0184030},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170433},
  pages     = {e0184030},
  year      = {2017},
  abstract  = {Imprinted genes show parent-specific activity (functional haploidy), which makes them particularly vulnerable to epigenetic dysregulation. Here we studied the methylation profiles of oppositely imprinted genes at single DNA molecule resolution by two independent parental allele-specific deep bisulfite sequencing (DBS) techniques. Using Roche (GSJunior) next generation sequencing technology, we analyzed the maternally imprinted MEST promoter and the paternally imprinted MEG3 intergenic (IG) differentially methylated region (DMR) in fetal cord blood, adult blood, and visceral adipose tissue. Epimutations were defined as paternal or maternal alleles with >50\% aberrantly (de)methylated CpG sites, showing the wrong methylation imprint. The epimutation rates (range 2-66\%) of the paternal MEST and the maternal MEG3 IG DMR allele, which should be completely unmethylated, were significantly higher than those (0-15\%) of the maternal MEST and paternal MEG3 alleles, which are expected to be fully methylated. This hypermethylation of the non-imprinted allele (HNA) was independent of parental origin. Very low epimutation rates in sperm suggest that HNA occurred after fertilization. DBS with Illumina (MiSeq) technology confirmed HNA for the MEST promoter and the MEG3 IG DMR, and to a lesser extent, for the paternally imprinted secondary MEG3 promoter and the maternally imprinted PEG3 promoter. HNA leads to biallelic methylation of imprinted genes in a considerable proportion of normal body cells (somatic mosaicism) and is highly variable between individuals. We propose that during development and differentiation maintenance of differential methylation at most imprinting control regions may become to some extent redundant. The accumulation of stochastic and environmentally-induced methylation errors on the non-imprinted allele may increase epigenetic diversity between cells and individuals.},
  language  = {en}
}
@article{PrellSenPotabattulaetal.2022,
  author    = {Prell, Andreas and Sen, Mustafa Orkun and Potabattula, Ramya and Bernhardt, Laura and Dittrich, Marcus and Hahn, Thomas and Schorsch, Martin and Zacchini, Federica and Ptak, Grazyna Ewa and Niemann, Heiner and Haaf, Thomas},
  title     = {Species-specific paternal age effects and sperm methylation levels of developmentally important genes},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {4},
  issn      = {2073-4409},
  doi       = {10.3390/cells11040731},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262301},
  year      = {2022},
  abstract  = {A growing number of sperm methylome analyses have identified genomic loci that are susceptible to paternal age effects in a variety of mammalian species, including human, bovine, and mouse. However, there is little overlap between different data sets. Here, we studied whether or not paternal age effects on the sperm epigenome have been conserved in mammalian evolution and compared methylation patterns of orthologous regulatory regions (mainly gene promoters) containing both conserved and non-conserved CpG sites in 94 human, 36 bovine, and 94 mouse sperm samples, using bisulfite pyrosequencing. We discovered three (NFKB2, RASGEF1C, and RPL6) age-related differentially methylated regions (ageDMRs) in humans, four (CHD7, HDAC11, PAK1, and PTK2B) in bovines, and three (Def6, Nrxn2, and Tbx19) in mice. Remarkably, the identified sperm ageDMRs were all species-specific. Most ageDMRs were in genomic regions with medium methylation levels and large methylation variation. Orthologous regions in species not showing this age effect were either hypermethylated (>80\%) or hypomethylated (<20\%). In humans and mice, ageDMRs lost methylation, whereas bovine ageDMRs gained methylation with age. Our results are in line with the hypothesis that sperm ageDMRs are in regions under epigenomic evolution and may be part of an epigenetic mechanism(s) for lineage-specific environmental adaptations and provide a solid basis for studies on downstream effects in the genes analyzed here.},
  language  = {en}
}