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Paternal Age Effects on Sperm FOXK1 and KCNA7 Methylation And Human Molecular Genetics, 2016, Vol. 25, No. 22 4996–5005 doi: 10.1093/hmg/ddw328 Advance Access Publication Date: 23 September 2016 Original Article ORIGINAL ARTICLE Paternal age effects on sperm FOXK1 and KCNA7 methylation and transmission into the next generation Stefanie Atsem1,†, Juliane Reichenbach1,†, Ramya Potabattula1,†, Marcus Dittrich1, Caroline Nava2, Christel Depienne2,3, Lena Bo¨hm1, Simone Rost1, Thomas Hahn4, Martin Schorsch4, Thomas Haaf1,* and Nady El Hajj1,* 1Institute of Human Genetics, Julius-Maximilians University, Wu¨ rzburg, Germany, 2INSERM, U 1127, CNRS UMR 7225, Sorbonne Universite´s, UPMC Univ Paris, Institut du Cerveau et de la Moelle e´pinie`re, ICM, Paris, France, 3De´partement de Me´dicine translationnelle et Neuroge´ne´tique, IGBMC, CNRS UMR 7104/INSERM U964/ Universite´ de Strasbourg, Illkirch, France and 4Fertility Center, Wiesbaden, Germany *To whom correspondence should be addressed at: Nady El Hajj, Institute of Human Genetics, Julius-Maximilians-Universitat€ Wu¨ rzburg, Biozentrum, Am Hubland, 97074 Wu¨ rzburg, Germany. Tel: þ49 931 3188796; Fax: þ49 931 3187398; Email: [email protected] or to Professor Dr. Thomas Haaf, Institute of Human Genetics, Julius-Maximilians-Universitat€ Wu¨ rzburg, Biozentrum, Am Hubland, 97074 Wu¨ rzburg, Germany. Tel: þ49 931 3188738; Fax: þ49 931 3187398; Email: [email protected] Abstract Children of older fathers carry an increased risk for developing autism and other disorders. To elucidate the underlying mechanisms, we investigated the correlation of sperm DNA methylation with paternal age and its impact on the epigenome of the offspring. Methylation levels of nine candidate genes and LINE-1 repeats were quantified by bisulfite pyrosequencing in sperm DNA of 162 donors and 191 cord blood samples of resulting children (conceived by IVF/ICSI with the same sperm samples). Four genes showed a significant negative correlation between sperm methylation and paternal age. For FOXK1 and KCNA7, the age effect on the sperm epigenome was replicated in an independent cohort of 188 sperm samples. For FOXK1, paternal age also significantly correlated with foetal cord blood (FCB) methylation. Deep bisulfite sequencing and allele- specific pyrosequencing allowed us to distinguish between maternal and paternal alleles in FCB samples with an informative SNP. FCB methylation of the paternal FOXK1 allele was negatively correlated with paternal age, whereas maternal allele was unaffected by maternal age. Since FOXK1 duplication has been associated with autism, we studied blood FOXK1 methylation in 74 children with autism and 41 age-matched controls. The FOXK1 promoter showed a trend for accelerated demethylation in the autism group. Dual luciferase reporter assay revealed that FOXK1 methylation influences gene expression. Collectively, our study demonstrates that age-related DNA methylation changes in sperm can be transmitted to the next generation and may contribute to the increased disease risk in offspring of older fathers. † The authors wish it to be known that, in their opinion, the first three authors should be regarded as co-first authors. Received: July 26, 2016. Revised: September 16, 2016. Accepted: September 21, 2016 VC The Author 2016. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 4996 Human Molecular Genetics, 2016, Vol. 25, No. 22 | 4997 Introduction Results A growing trend for delayed parenthood is evident in Western Genes with paternal age-related methylation changes in countries where many couples postpone their wish for children sperm up to their late thirties. Fathers older than 35 years accounted for 25% of birth in 1993 and for 40% in 2003 (1). Both prospective A previous study (22) identified several genes which showed a parents and physicians are mainly concerned about advanced correlation between paternal age and sperm methylation. We maternal age and increasing oocyte aneuploidy rates which selected 9 previously reported age-related genes, DRD4, NCOR2, cause fertility problems, spontaneous abortions and children NKX2-5, KCNA7, GET4, DMPK, PDE4C, TNXB, and FOXK1, because with Down syndrome (2). Because of life-long spermatogenesis of their association with neuropsychiatric and other disorders and potential male fertility, the influence of paternal age on re- (Supplementary Material, Table S5). None of the studied genes, production and offspring health is usually underestimated. apart from PDE4C, was previously reported to exhibit age- Accumulating evidence from animal and human epidemio- associated methylation changes in blood cells or any other logical studies also suggests effects of paternal factors, most im- somatic tissue. Repetitive LINE-1 elements, which comprise portantly age, on the development of the offspring (3). It has approximately 17% of the human genome, were used as a surro- long been recognized that male age at conception is associated gate marker for global methylation (23). Bisulfite pyrosequenc- with an increased risk for de novo mutations causing achondro- ing was used to quantify average methylation levels of these 10 plasia and other rare monogenetic disorders (4). More recently, loci in 162 IVF/ICSI sperm samples (cohort 1) which had led to a pregnancy. Four genes, DMPK, FOXK1, KCNA7, and NCOR2, there has been considerable interest in paternal age as a risk showed significant negative correlation with paternal age (Table factor for neurodevelopmental disorders including autism, bi- 1; Fig. 1, upper panel). FOXK1 and KCNA7 revealed the strongest polar disorder, and schizophrenia (5–9). Paternal age also has an hypomethylation with correlation coefficients of À0.35 and À0. effect on learning and cognition in children (10). One widely ac- 34, respectively. The remaining five genes and LINE-1 elements cepted explanation for these paternal age effects is that the rate did not show a significant correlation between average methyl- of de novo mutations is increasing with age. Spermatogenesis is ation (of the entire target region) and paternal age, although a a life-long process and the number of spermatogonial cell divi- few individual CpG sites, for example CpG2 (P ¼ 0.05) in the sions prior to spermiogenesis increase from 35 at puberty LINE-1 assay, were borderline significant. We then extended our to >800 at 50 years. During each replication cycle (every 2–3 analysis by using multivariate regression models, to adjust for weeks) and cell division, genetic mutations occur, continuously the cofactor sperm concentration. This analysis also revealed a increasing the mutational load in the sperm of older males (11). strong negative correlation for FOXK1, KCNA7, and NCOR2 but However, genetic de novo mutations explain only part of the in- not for DMPK (Supplementary Material, Table S6). Before study- creased disease risk in children of older fathers. Despite enor- ing single sperm methylation of FOXK1 and KCNA7, bisulfite mous research efforts (GWAS), neuropsychiatric and other pyrosequencing was performed in 188 independent sperm sam- complex disorders with paternal age effect display missing heri- ples (cohort 2) that did not lead to pregnancy after IVF/ICSI. tability. During each cell division not only the DNA itself, but Consistent with the results of cohort 1, both FOXK1 (À0.25; 0. also the epigenetic modifications must be copied to the daugh- 001) and KCNA7 (À0.37, P < 0.001) methylation negatively corre- ter cells. Since biochemical copying of the epigenetic informa- lated with paternal age. tion is much more error-prone than DNA replication (4,12), it is For single allele DBS analysis, we selected 13 sperm samples plausible to assume that aging male germ cells accumulate of younger (25–35 years) and 13 of older (40–55 years) donors many more epigenetic than DNA sequence changes. Epigenetic from cohort 1. Figure 2 presents the distribution of single allele changes, mainly in DNA methylation, during aging have been methylation patterns for FOXK1 and KCNA7. Sperm with 0 meth- extensively studied and associated with age-related diseases ylated CpGs are fully demethylated; sperm with five methylated (13–15). Specific DNA methylation alterations have been found CpGs in FOXK1 and 12 in KCNA7, respectively, are fully methyl- in the brain of individuals with neurodevelopmental diseases ated. For both genes, sperm of younger donors display an enor- and linked to the developmental trajectories exhibiting mous (0–100%) methylation variation with most alleles (reads) dynamic methylation changes during foetal brain development exhibiting mixed methylation patterns (50–90%). In the sperm (16–18). of older donors methylation variation is drastically reduced and Elegant mouse studies provide a link between age- shows a trend towards hypomethylation (0–20% for FOXK1 and associated sperm methylation alterations and changes in brain 10–40% for KCNA7). Consistent with bisulfite pyrosequencing gene expression, methylation, and behaviour in the offspring of (Table 1), average methylations levels (of all sequence reads of a older mice (19,20). These findings are consistent with the view sample) correlated significantly with paternal age for both that sperm epigenetic marks can transmit paternal effects
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