Genome-wide 5-hydroxymethylcytosine modification pattern is a novel epigenetic feature of globozoospermia

Abstract

Discovery of 5-hydroxymethylcytosine (5hmC) in mammalian genomes has excited the field of epigenetics, but information on the genome-wide distribution of 5hmC is limited. Globozoospermia is a rare but severe cause of male infertility. To date, the epigenetic mechanism, especially 5hmC profiles involved in globozoospermia progression, remains largely unknown. Here, utilizing the chemical labeling and biotin-enrichment approach followed by Illumina HiSeq sequencing, we showed that (i) 6664, 9029 and 6318 genes contain 5hmC in normal, abnormal, and globozoospermia sperm, respectively; (ii) some 5hmC-containing genes significantly involves in spermatogenesis, sperm motility and morphology, and gamete generation; (iii) 5hmC is exclusively localized in sperm intron; (iv) approximately 40% imprinted genes have 5hmC modification in sperm genomes, but globozoospermia sperm exhibiting a large portion of imprinted genes lose the 5hmC modification; (v) six imprinted genes showed different 5hmC patterns in abnormal sperm (GDAP1L1, GNAS, KCNK9, LIN28B, RB1, RTL1), and five imprinted genes showed different 5hmC patterns in globozoospermia sperm (KCNK9, LIN28B, RB1, SLC22A18, ZDBF2). These results suggested that differences in genome-wide 5hmC patterns may in part be responsible for the sperm phenotype. All of this may improve our understanding of the basic molecular mechanism underlying sperm biology and the etiology of male infertility.

Induction of Chronic Inflammation and Altered Levels of DNA Hydroxymethylation in Somatic and Germinal Tissues of CBA/CaJ Mice Exposed to 48Ti Ions

“…At 6 months postirradiation, the effects of 1 GeV/n 48 Ti ions on levels of global 5mC and 5hmC in the testes of exposed mice are similar to those found in the lung of the same mouse. As mentioned previously, altered DNA methylation plays an important role in male infertility ( 62 – 64 ), germ cell tumors ( 59 , 60 ), and transgeneration effects ( 65 , 78 ). Hence, our data provide critical information for conducting further studies to investigate the potential induction of these untoward outcomes on male germinal cells from exposure to 1 GeV/n 48 Ti ions.…”

“…Relating to DNA methylation, it has been well recognized that it is one of the key epigenetic events that plays a critical role in carcinogenesis, both initiation and promotion, in somatic and germinal cells ( 59 , 60 ), and other untoward health outcomes ( 14 ) including male-mediated developmental toxicology ( 61 ), male infertility ( 62 – 64 ), and transgeneration effects ( 65 , 66 ). Furthermore, a high level of 5mC (hypermethylation) has been linked to gene silencing ( 59 , 67 ); while a reduction in global levels of 5hmC has been associated with cancer development ( 68 ).…”

DNA hydroxymethylation rate in the AChE and HoxC4 promoter associated with human sperm quality

“…Interestingly, the 5hmC levels on the gene bodies and proximal promoters of highly expressed genes were markedly higher than those of genes expressed at lower levels in different stages of mouse spermatogenesis, indicating that 5hmC plays an important role in active gene transcription in spermatogenesis (Gan et al., ). Alteration in 5hmc has been found to exist widely in globozoospermia spermatozoa (Wang et al., ) and the spermatozoa from infertile men (Efimova et al., ). We recently reported the presence of genome‐wide alteration of 5hmc in the spermatozoa from the men exposed to bisphenol A (BPA; Zheng et al., ), a widely studied endocrine‐disrupting chemical (EDC) which has a power to reduce human sperm quality, according to the human epidemiologic studies (Li et al., ).…”

Epigenetics and male reproduction: the consequences of paternal lifestyle on fertility, embryo development, and children lifetime health

“…Gan et al showed that the highly ordered 5hmC alterations are critical for the differentiation of spermatogenic cells in the mouse [ 35 ]. Recently, Wang et al for the first time compared 5-hydroxymethylcytosine profiles in normal, abnormal, and globozoospermia sperms, identifying 6664, 9029, and 6318 genes containing 5hmC, respectively [ 36 ]. In addition, since some 5hmC-containing genes are significantly involved in spermatogenesis, sperm motility, and morphology, the authors suggested that the 5hmC distribution differences may contribute to the sperm phenotype [ 36 ].…”