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.
Highlights
50–80 million people worldwide are affected by infertility; of these cases, 50% are caused by male factors and most of them have asthenospermia
VDAC2 mRNA expression was compared between GC-2spd cells with and without 5-Aza-CdR through qRT-PCR analysis, and predicted the VDAC2 promoter region
After constructing plasmids containing the VDAC2 gene promoter, dual-luciferase activity was detected to verify the activity of the VDAC2 promoter region in GC-2spd cells
Summary
50–80 million people worldwide are affected by infertility; of these cases, 50% are caused by male factors and most of them have asthenospermia. Abnormal protein expression and epigenetic modification changes may negatively affect sperm motility and morphology, thereby inducing male infertility. VDAC2 plays an important role in spermatogenesis and male infertility[17]. It is abundant in the mitochondria outer dense fibers, which are close to the dynein light chain Tctex-type 1; it regulates sperm motion and sperm tail structural integrity through interaction with Tctex or microtubule-associated proteins[15,18,19]. Abnormal VDAC2 expression is a potential cause of low sperm motility. Just like the unclear molecular mechanism in VDAC3-lacking mice with normal parameters except for progressive motility, the underlying mechanism remains unclear[22]
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