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Copy Number Gain of VCX, X-Linked Multi-Copy Gene, Leads to Cell Proliferation and Apoptosis During Spermatogenesis

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Copy Number Gain of VCX, X-Linked Multi-Copy Gene, Leads to Cell Proliferation and Apoptosis During Spermatogenesis www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 48 Research Paper Copy number gain of VCX, X-linked multi-copy gene, leads to cell proliferation and apoptosis during spermatogenesis Juan Ji1,2,4,*, Yufeng Qin3,*, Rong Wang5,*, Zhenyao Huang1,2, Yan Zhang1,2, Ran Zhou1,2, Ling Song1,2, Xiufeng Ling4, Zhibin Hu1,6, Dengshun Miao1,5, Hongbing Shen1,6, Yankai Xia1,2, Xinru Wang1,2, Chuncheng Lu1,2 1State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China 2Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China 3Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA 4Department of Children Health Care, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China 5Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, China 6Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China *These authors contributed equally to this work and joint first authors Correspondence to: Chuncheng Lu, email: [email protected] Keywords: copy number variations, non-obstructive azoospermia Received: April 08, 2016 Accepted: September 25, 2016 Published: October 01, 2016 ABSTRACT Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. In recent years there has been increasing evidence to implicate the participation of X chromosome in the process of spermatogenesis. To uncover the roles of X-linked multi-copy genes in spermatogenesis, we performed systematic analysis of X-linked gene copy number variations (CNVs) and Y chromosome haplogrouping in 447 idiopathic NOA patients and 485 healthy controls. Interestingly, the frequency of individuals with abnormal level copy of Variable charge, X-linked (VCX) was significantly different between cases and controls after multiple test correction (p = 5.10 × 10−5). To discriminate the effect of gain/loss copies in these genes, we analyzed the frequency of X-linked multi-copy genes in subjects among subdivided groups. Our results demonstrated that individuals with increased copy numbers of Nuclear RNA export factor 2 (NXF2) (p = 9.21 × 10−8) and VCX (p = 1.97 × 10−4) conferred the risk of NOA. In vitro analysis demonstrated that increasing copy number of VCX could upregulate the gene expression and regulate cell proliferation and apoptosis. Our study establishes a robust association between the VCX CNVs and NOA risk. INTRODUCTION genetic causes, especially the Yq microdeletions, in male infertility are well established so far [2–4]. However, Male infertility, a common reproductive disorder, X-linked genes and their potential effects on male is estimated to affect approximately one-sixth of couples infertility are less well understood. worldwide [1]. A significant proportion of male infertility Originally, it was thought that mammalian X is accompanied by idiopathic azoospermia, most often chromosomes were enriched in spermatogenesis genes presenting as non-obstructive azoospermia (NOA), expressed before meiosis and deficient after meiosis [5–7]. defined as the absence of sperm in the ejaculate without The paucity of post-meiotic genes on the X chromosome the obstruction of reproductive tract. Certain pathogenic has been interpreted as a consequence of Meiotic Sex www.impactjournals.com/oncotarget 78532 Oncotarget Chromosome Inactivation (MSCI) [8, 9]. Recently, suggested that the genetic background, mainly Y-hgs, may Zhang et al. noticed that some testis-specific genes could not affect our results of the present association study. be detected throughout all stages of spermatogenesis, indicating that they escape MSCI [10]. And it was X-linked multi-copy gene copy number estimated that 70% of these genes were expressed in variations and NOA post-meiotic stages [10]. Interestingly, the majority of these genes are multi-copy X-linked genes, moreover, the Overall, seven X-linked gene copy numbers more copies of a gene, the higher chance to escape from were determined in 447 NOA patients and 485 healthy X inactivation, accounting for higher expression level controls using the AccuCopy method. The distributions of of multi-copy X-linked genes than that of single-copy copy number of seven genes in case and control groups X-linked genes [11]. were shown in Table 2. We found that the frequency of With the rapid development of genome-scanning individuals with abnormal copy number of NXF2 (OR, technologies [12], the structural variations in human 2.46, 95% CI 1.15−5.25, p = 1.66 × 10−2) and VCX (OR, genome were emerged and fully uncovered [13]. One 2.53, 95% CI 1.60−4.02, p = 5.10 × 10−5) in NOA group type of structural variations is copy number variation was significantly higher than that in control group, while (CNV) that generally defined as a segment of DNA the frequency of FAM47 (OR, 0.27, 95% CI 0.07−0.95, (1 kb or larger), presenting at a variable copy number p = 2.89 × 10−2) was significantly lower in NOA groups compared to a reference genome [13]. It has been (Table 2). However, only the association between VCX and demonstrated that CNV was associated with numerous NOA risk retained after Bonferroni correction (Table 2). diseases [14], including Alzheimer’s disease, Parkinson To discriminate the effects of copy number gain or disease, congenital scoliosis [15–17]. Recently, increasing loss in these genes on NOA, we subdivided the subjects evidence implied that CNVs were crucial determinant of into three subgroups: the common level copy group, the less spermatogenesis and might contribute to male infertility than common level group and the more than common level [18–20], while little is known about the relationship group. The detailed distributions were shown in Table 3. between X-linked gene CNVs and NOA. Our results demonstrated that 10 out of 485 (~2%) was To systematically analyze X-linked gene CNVs found with decreased NXF2 copy number in the control and their effects on NOA, we performed comprehensive group, while no one was found in the NOA group. On the molecular analyses in 447 idiopathic NOA men and 485 contrary, 22 out of 447 (~5%) were found with increased healthy controls. Eventually, the CNVs of Variable charge, NXF2 copy number in NOA group, while no one was X-linked (VCX) and Nuclear RNA export factor 2 (NXF2) found in the control group. Namely, decreased NXF2 copy were found to be associated with NOA, subsequently number showed protective against NOA (p = 2.20 × 10−3), in vitro analysis was carried out to clarify the potential role while increased copy number conferred the risk of NOA of VCX in spermatogenesis. (p = 9.21 × 10−8). To the VCX gene, the frequency of individuals with RESULTS increased VCX gene copy number in the NOA group (56 out of 447, ~13%) was significantly higher than that in Characteristics and clinical parameters of the the fertility/normozoospermia group (27 out of 485, ~6%) −4 study population (OR, 2.46, 95% CI 1.52−3.97, p = 1.97 × 10 ). Our study included 447 NOA patients and 485 VCX expression in germ cells and seminal fertile controls. The mean age and BMI in control group plasma were 30.1 and 24.3, and in case group was 29.5 and 23.3, respectively (Table 1). There were no significant To explore the transfection efficiency of VCX in 293 differences identified between the case and control groups and GC cell lines, we measured the VCX expression before with regard to their age, smoking and drinking status. and after transfection. As it showed (Supplementary Material, However, significant differences were identified in BMI Figure S1A–S1C), the VCX expression was significantly between cases and controls (Table 1). increased after transfected. Besides, to investigate whether the VCX copy number gains lead to mRNA overexpression, Y-hg distribution between the case and control the mRNA level of VCX in seminal plasma was detected, groups and we found that the mRNA expression of VCX was increased in NOA (Supplementary Figure S1D). To test for the potential influence of genetic backgrounds, 14 Y chromosome binary markers were Effects of VCX on cell proliferation, cell used to define 14 Y-hgs in patients and normal subjects apoptosis and cell cycle (controls). No significant difference in the Y-hg distribution was found between the healthy control group and the NOA By searching Database of Genomic Variants (DGV), case group (Supplementary Material, Table S1), which we found that most frequent structure variations in NXF2 www.impactjournals.com/oncotarget 78533 Oncotarget Table 1: Main characteristics and clinical parameters of study subjects Variables Controls (n = 485) Cases (n = 447) Age (years) [mean ± SD] 30.1 ± 4.7 29.5 ± 5.0 Smoking Status [n, (%)] Never Smokers 329 (68%) 318 (71%) Ever Smokers 156 (32%) 129 (29%) Alcohol consumption [n, (%)] Never drinkers 332 (68%) 313 (70%) Ever drinkers 153 (32%) 134 (30%) BMI (kg/m2) [mean ± SD] 24.3 ± 3.2 23.3 ± 3.0a aP < 0.05 for Student’s t test and Wilcoxon rank sum test for selected characteristics distributions between the control and case groups. Table 2: Distributions of CSAG, CTAG, CT45, FAM47, H2AFB1, NXF2 and VCX gene copy numbers in subjects Fertile Controls (485) Infertile Cases (447) Genea
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