title: Epigenetic disruption of the PIWI pathway in human spermatogenic disorders.
abstract: 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.
authors.affiliation: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, 08908 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.forename: Humberto J
authors.initials: HJ
authors.lastname: Ferreira
authors.forename: Lluís
authors.initials: L
authors.lastname: Bassas
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonache
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Sara
authors.initials: S
authors.lastname: Larriba
mesh_terms: D000328:Adult; D060565:Argonaute Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D015536:Down-Regulation; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000235:genetics; D054331:Sertoli Cell-Only Syndrome / Q000235:genetics / Q000473:pathology; D013091:Spermatogenesis; D013094:Spermatozoa / Q000378:metabolism* / Q000473:pathology
chemical_list: D060565:Argonaute Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C486868:PIWIL2 protein, human; C580566:TDRD1 protein, human; D012313:RNA; D004247:DNA