Abstract
BackgroundDNA methylation analysis is useful for investigation of male fertility in mammals, whereas the reliance on tissues limits the research on human. We have previously found the presence of high concentration of cell-free seminal DNA (cfsDNA) in human semen. We proposed that some testis and epididymis-specific methylated promoters could be detected in human cfsDNA, and thus hold promise as noninvasive epigenetic biomarkers for male infertility, of which most cases are caused by defects in testicular sperm production or epididymal sperm maturation.ResultsThe ejaculate of successfully vasectomized men does not contain any secretion from testis and epididymis. Here we compared genome-wide promoter methylation profiles in cfsDNA between health donors and post-vasectomy men. Promoters of 367 testis and epididymis-specific hypomethylated genes and 134 hypermethylated genes were identified. Subsequent validation by Methyl-DNA immunoprecipitation and MethyLight analysis confirmed the result of promoter microarray. Gene Ontology analysis revealed many genes involved in male reproduction.ConclusionWe detected the testis and epididymis-specific methylated promoters in human cfsDNA, which may be used for noninvasive epigenetic biomarkers for the study and diagnosis of male infertility.
Highlights
DNA methylation analysis is useful for investigation of male fertility in mammals, whereas the reliance on tissues limits the research on human
The averaged cell-free seminal DNA (cfsDNA) concentration of Nor was about quadruple of PV, which suggests more than 70% cfsDNA originates from testis and epididymis
Our results demonstrate that there are a number of promoters of testis and epididymis-specific hypoand hypermethylated genes in cfsDNA, providing a foundation for developing noninvasive biomarkers for studying the epigenetic mechanism and clinical diagnosis of male infertility, of which most conditions are impaired testicular spermatogenesis and epididymal sperm maturation
Summary
DNA methylation analysis is useful for investigation of male fertility in mammals, whereas the reliance on tissues limits the research on human. Cell-free nucleic acids, including DNA and RNA, exist ubiquitously as cell-free or being absorbed at the cell surface of living organisms [1] They are found to be released via apoptotic or necrotic cells, and be actively secreted by living cells [1,2]. Given that human ejaculate is a mixture secreted from bilateral testes, epididymides, seminal vesicles, bulbourethral glands, and the prostate [11], cfsDNA should contain DNA epigenetic information of these organs. These DNA epigenetic information should be undetectable in the blood, because DNA should not pass the physical barrier between the blood and the male reproduction system including blood-testis barrier and blood-epididymis barrier
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