Abnormal Hypermethylation of the VDAC2 Promoter is a Potential Cause of Idiopathic Asthenospermia in Men

Abstract

This study aimed to explore the association between the methylation status of the VDAC2 gene promoter region and idiopathic asthenospermia (IAS). Twenty-five IAS patients and 27 fertile normozoospermia (NZ) were involved. GC-2spd cells were treated with different concentrations of 5-aza-2′-deoxycytidine (5-Aza-CdR) for 24 h and 48 h. qRT-PCR was conducted to reveal whether or not VDAC2 expression was regulated by methylated modification. A dual-luciferase activity detection was used to verify VDAC2 promoter activity in GC-2spd cells. Bisulphite genomic sequence was used to analyse DNA methylation of the VDAC2 promoter. The results showed that VDAC2 expression was significantly increased after treated with 5-Aza-CdR. A strong activity of the promoter (−2000 bp to +1000 bp) was detected by dual-luciferase activity detection (P < 0.05). The bisulphite genomic sequencing and correlation analysis showed that sperm motility was positively associated with the methylation pattern of uncomplete methylation and mild hypermethylation, and negatively related to the percentage of moderate methylation. In conclusion, high methylation of the VDAC2 promoter CpGs could be positively correlated with low sperm motility. Abnormal methylation of VDAC2 promoter may be a potential cause to idiopathic asthenospermia.

Freezability biomarkers in bull epididymal spermatozoa

“…This protein has a critical role in the transportation of ions and small molecules in spermatozoa through the lipid bilayer 42,43 . Several studies demonstrated that abnormal activity and alteration of this protein concentration have inimical effects on sperm function and fertility via alteration of ionic influx 44–46 . Since freezing/thawing step is associated with increased osmotic stress mediated via ionic imbalance, thus VDAC2 can be a candidate marker for predicting sperm freezability.…”

Is the Secret of VDAC Isoforms in Their Gene Regulation? Characterization of Human VDAC Genes Expression Profile, Promoter Activity, and Transcriptional Regulators

“…The activity of VDAC2 promoter in a mammal’s developing ovary triggered by GATA1 and Cellular and viral myb-like transcriptional regulators (MYBL2) transcription factors lead to autophagy inhibition confirming its relevant role in cell survival [ 29 ]. In human male abnormal hypermethylation of VDAC2 promoter correlated with idiopathic asthenospermia while in complete unmethylation or mild hypermethylation, sperm motility improved confirming the role of VDAC2 expression in human spermatozoa [ 30 ]. The increased expression level of the VDAC1 transcript was also induced by a lncRNA through enhancement of H3K4me3 levels in its promoter, leading to apoptosis of placental trophoblast cells during early recurrent miscarriage [ 31 ].…”

Epigenetic dynamics and interplay during spermatogenesis and embryogenesis: implications for male fertility and offspring health

“…The hypermethylation at the promoter region of the MTHFR has shown to down regulate the MTHFR expression, and as a result its enzymatic activity is reduced, leading to non-obstructive azoospermia (NOA) and potentially idiopathic infertility [ 57 – 59 ]. Likewise, hypermethylation of VDAC2 promoter region might reduce sperm motility, ultimately result in idiopathic asthenospermia [ 60 ]. In the regions of regulatory promoters, which are associated with the silencing of tumour suppressor genes, the hypermethylation can lead to testicular germ cell tumours [ 61 ].…”