Paternal age effects on sperm FOXK1 and KCNA7 methylation and transmission into the next generation.
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.
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Stefanie
S
Atsem
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Juliane
J
Reichenbach
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Ramya
R
Potabattula
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Marcus
M
Dittrich
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
Caroline
C
Nava
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.|Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France
Christel
C
Depienne
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Lena
L
Böhm
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Simone
S
Rost
Fertility Center, Wiesbaden, Germany.
Thomas
T
Hahn
Fertility Center, Wiesbaden, Germany.
Martin
M
Schorsch
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Thomas
T
Haaf
Institute of Human Genetics, Julius-Maximilians University, Würzburg, Germany.
Nady
N
El Hajj
D000328:Adult; D000368:Aged; D000483:Alleles; D001321:Autistic Disorder / Q000097:blood / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D017218:Cordocentesis; D004247:DNA / Q000097:blood / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010331:Paternal Age; D011401:Promoter Regions, Genetic; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics*; D013094:Spermatozoa / Q000378:metabolism / Q000502:physiology*
C495879:FOXK1 protein, human; D051858:Forkhead Transcription Factors; C431140:KCNA7 protein, human; D051637:Shaker Superfamily of Potassium Channels; D004247:DNA