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Abstract
Data about the entire sperm DNA methylome are limited to two sperm donors whereas studies dealing with a greater number of subjects focused only on a few genes or were based on low resolution arrays. This implies that information about what we can consider as a normal sperm DNA methylome and whether it is stable among different normozoospermic individuals is still missing. The definition of the DNA methylation profile of normozoospermic men, the entity of inter-individual variability and the epigenetic characterization of quality-fractioned sperm subpopulations in the same subject (intra-individual variability) are relevant for a better understanding of pathological conditions. We addressed these questions by using the high resolution Infinium 450K methylation array and compared normal sperm DNA methylomes against somatic and cancer cells. Our study, based on the largest number of subjects (n = 8) ever considered for such a large number of CpGs (n = 487,517), provided clear evidence for i) a highly conserved DNA methylation profile among normozoospermic subjects; ii) a stable sperm DNA methylation pattern in different quality-fractioned sperm populations of the same individual. The latter finding is particularly relevant if we consider that different quality fractioned sperm subpopulations show differences in their structural features, metabolic and genomic profiles. We demonstrate, for the first time, that DNA methylation in normozoospermic men remains highly uniform regardless the quality of sperm subpopulations. In addition, our analysis provided both confirmatory and novel data concerning the sperm DNA methylome, including its peculiar features in respect to somatic and cancer cells. Our description about a highly polarized sperm DNA methylation profile, the clearly distinct genomic and functional organization of hypo- versus hypermethylated loci as well as the association of histone-enriched hypomethylated loci with embryonic development, which we now extended also to hypomethylated piRNAs-linked genes, provides solid basis for future basic and clinical research.
Highlights
Human spermatogenesis is an outstandingly complex biological process which requires the concerted action of several thousands of genes [1]
Given the paucity of data on intra- and inter-individual variability of sperm DNA methylation, we aimed to provide a detailed description based on the analysis of a total of 487,317 CpG sites
Given that the swim-up fraction, being enriched in the best quality spermatozoa, is the one used for assisted reproductive techniques, we aimed to provide a detailed description of genome wide DNA methylation profile of these cells
Summary
Human spermatogenesis is an outstandingly complex biological process which requires the concerted action of several thousands of genes [1]. An interesting feature of this biological process is the extremely large inter-individual variability of sperm production in healthy fertile men. The entity of this variation is well illustrated by a large recent study, reporting that total sperm number in the so called normal range (defined as 5th -95th percentile), varies from 40 millions to several hundred millions [2]. Enough, despite the same testicular environment, biochemical markers [7,8] as well as DNA integrity [9,10,11,12] show differences in distinct sperm fractions belonging to the same individual It is still unknown whether these fractions show differences in their methylation level
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