期刊
PLOS ONE
卷 7, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0047892
关键词
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资金
- Fondo de Investigaciones Sanitarias (FIS/FEDER) [PI08-1345, PI09-1727]
- European Research Council (ERC) Advanced Grant EPINORC [268626]
- Ministerio de Ciencia e Innovacion (MICINN) [SAF2011-22803]
- Cellex Foundation
- Health Department of the Catalan Government (Generalitat de Catalunya)
- Sistema Nacional de Salud (SNS) [CES09/020]
- Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/33887/2009]
- ICREA Funding Source: Custom
- Fundação para a Ciência e a Tecnologia [SFRH/BD/33887/2009] Funding Source: FCT
Epigenetic changes are involved in a wide range of common human diseases. Although DNA methylation defects are known to be associated with male infertility in mice, their impact on human deficiency of sperm production has yet to be determined. We have assessed the global genomic DNA methylation profiles in human infertile male patients with spermatogenic disorders by using the Infinium Human Methylation27 BeadChip. Three populations were studied: conserved spermatogenesis, spermatogenic failure due to germ cell maturation defects, and Sertoli cell-only syndrome samples. A disease-associated DNA methylation profile, characterized by targeting members of the PIWI-associated RNA (piRNA) processing machinery, was obtained. Bisulfite genomic sequencing and pyrosequencing in a large cohort (n = 46) of samples validated the altered DNA methylation patterns observed in piRNA-processing genes. In particular, male infertility was associated with the promoter hypermethylation-associated silencing of PIWIL2 and TDRD1. The downstream effects mediated by the epigenetic inactivation of the PIWI pathway genes were a defective production of piRNAs and a hypomethylation of the LINE-1 repetitive sequence in the affected patients. Overall, our data suggest that DNA methylation, at least that affecting PIWIL2/TDRD1, has a role in the control of gene expression in spermatogenesis and its imbalance contributes to an unsuccessful germ cell development that might explain a group of male infertility disorders.
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