• PMID: 29095993
• Gene Name: MAEL
• Condition: Spermatogenetic failure, Male infertility
• Association: Associated
• Mutation: Hypermethylation of a specific region (-131 to +177)
• Population size: 38
• Population details: 38 (26 NOA and HS, 12 with obstructive azoospermia and normal spermatogenesis)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Spermatogenetic failure, Male infertility

MAEL promoter hypermethylation is associated with de-repression of LINE-1 in human hypospermatogenesis

Cheng YS, Wee SK, Lin TY, Lin YM.

STUDY QUESTION: Does the hypermethylation of the maelstrom spermatogenic transposon silencer (MAEL) promoter and subsequent de-repression of transposable elements represent one of the causes of spermatogenic failure in infertile men? SUMMARY ANSWER: Experimental hypermethylation of a specific region (-131 to +177) of the MAEL promoter leads to decreased expression of MAEL with increased expression of the transposable element LINE-1 (L1) and in infertile men methylation of the MAEL promoter is associated with the severity of spermatogenic failure. WHAT IS KNOWN ALREADY: MAEL induces transposon repression in the male germline and is required for mammalian meiotic progression and post-meiotic spermiogenesis. Patients with non-obstructive azoospermia (NOA), defined as no sperm in the ejaculate due to spermatogenic failure, and histopathologically proven hypospermatogenesis (HS) is not uncommon and its etiology is largely unknown. STUDY DESIGN, SIZE, DURATION: Luciferase reporter assay and a targeted DNA methylation model were used to explore the effects of hypermethylation of MAEL promoter on gene expression. Germ cell-enriched testicular cells from infertile patients were used to determine the methylation levels of MAEL and expressions of MAEL and L1. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-six patients with histopathologically proven NOA and HS and 12 patients with obstructive azoospermia and normal spermatogenesis (NS) were enrolled in this study. Demographic and clinical information were obtained. The severity of HS was determined by a spermatogenic scoring system. The methylation levels of 26 CpGs in the MAEL promoter was measured, and quantitative real-time RT-PCR was used to determine the expressional levels of MAEL and L1. MAIN RESULTS AND THE ROLE OF CHANCE: Targeted DNA methylation of MAEL promoter suppressed MAEL expression and de-repressed L1 activity in vitro. Patients with HS had significantly higher mean methylation levels of 26 consecutive CpGs in the MAEL promoter, compared to patients with NS. The MAEL methylation levels were negatively correlated with MAEL transcript levels and higher methylation level of MAEL was associated with severe spermatogenic defect. L1 transcript level was significantly higher in patients with HS. No differences in age, frequency of testicular insults and genetic anomalies was noted between patients with high or low MAEL methylation levels. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Because of the difficulty in the use of human germ cells for study, the in vitro targeted DNA methylation model was performed by using human NCI-H358 cells to explore the effects of MAEL methylation on transposable elements activity. Because the germ cell-enriched testicular cells isolated from a testicular sample were relatively few, the purity of cell populations was not determined. WIDER IMPLICATIONS OF THE FINDINGS: Measurement of the methylation level of MAEL gene may be feasible to predict the severity of spermatogenic failure or the outcome of testicular sperm retrieval. STUDY FUNDING/COMPETING INTERESTS: This work was supported through grants from the Ministry of Science and Technology of Taiwan (100-2314-B-006-017) and National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH 20120266). The authors declare no conflicts of interest. CI - © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com FAU - Cheng, Yu-Sheng AU - Cheng YS AD - Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Wee, Shi-Kae AU - Wee SK AD - Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Lin, Tsung-Yen AU - Lin TY AD - Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.