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Epigenetic Inactivation of SOX30 Is Associated with Male Infertility and Offers a Therapy Target for Non-obstructive Azoospermia.

ABSTRACT: Non-obstructive azoospermia (NOA) is the most severe form of male infertility. However, the etiology of NOA is largely unknown, resulting in a lack of clinical treatments. Here, we performed a comparative genome-wide profiling of DNA methylation and identified SOX30 as the most notably hyper-methylated gene at promoter in testicular tissues from NOA patients. This hyper-methylation at promoter of SOX30 directly causes its silencing of expression in NOA. The reduced levels of SOX30 expression are correlated with severity of NOA disease. Deletion of Sox30 in mice uniquely impairs testis development and spermatogenesis with complete absence of spermatozoa in testes leading to male infertility, but does not influence ovary development and female fertility. The pathology and testicular size of Sox30 null mice highly simulate those of NOA patients. Re-expression of Sox30 in Sox30 null mice at adult age reverses the pathological damage of testis and restores the spermatogenesis. The re-presented spermatozoa after re-expression of Sox30 in Sox30 null mice have the ability to start a pregnancy. Moreover, the male offspring of Sox30 re-expression Sox30 null mice still can father children, and these male offspring and their children can live normally more than 1 year without significant difference of physical appearance compared with wild-type mice. In summary, methylated inactivation of SOX30 uniquely impairs spermatogenesis, probably causing NOA disease, and re-expression of SOX30 can successfully restore the spermatogenesis and actual fertility. This study advances our understanding of the pathogenesis of NOA, offering a promising therapy target for NOA disease.

SUBMITTER: Han F

PROVIDER: S-EPMC6926170 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Epigenetic Inactivation of SOX30 Is Associated with Male Infertility and Offers a Therapy Target for Non-obstructive Azoospermia.

Han Fei F Jiang Xiao X Li Zhi-Ming ZM Zhuang Xuan X Zhang Xi X Ouyang Wei-Ming WM Liu Wen-Bin WB Mao Cheng-Yi CY Chen Qing Q Huang Chuan-Shu CS Gao Fei F Cui Zhi-Hong ZH Ao Lin L Li Yan-Feng YF Cao Jia J Liu Jin-Yi JY

Molecular therapy. Nucleic acids 20191114

Non-obstructive azoospermia (NOA) is the most severe form of male infertility. However, the etiology of NOA is largely unknown, resulting in a lack of clinical treatments. Here, we performed a comparative genome-wide profiling of DNA methylation and identified SOX30 as the most notably hyper-methylated gene at promoter in testicular tissues from NOA patients. This hyper-methylation at promoter of SOX30 directly causes its silencing of expression in NOA. The reduced levels of SOX30 expression are ...[more]

PMID: 31835093

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Project description:BackgroundNon-obstructive azoospermia (NOA) is the most severe form of male infertility; more than half of the NOA patients are idiopathic. Although many NOA risk genes have been detected, the genetic factors for NOA in majority of the patients are unknown. In addition, it is difficult to retrieve sperm from these patients despite using the microsurgical testicular sperm extraction (microTESE) method. Therefore, we conducted this genetic study to identify the potential genetic factors responsible for NOA and investigate the sperm retrieval rate of microTESE for genetically deficient NOA patients.MethodsSemen analyses, sex hormone testing, and testicular biopsy were performed to categorize the patients with NOA. The chromosome karyotypes and Y chromosome microdeletion analyses were used to exclude general genetic factors. Whole exome sequencing and Sanger sequencing were performed to identify potential genetic variants in 51 patients with NOA. Hematoxylin and eosin staining (H&E) and anti-phosphorylated H2AX were used to assess the histopathology of spermatogenesis. Quantitative real time-polymerase chain reaction, western blotting, and immunofluorescence were performed to verify the effects of gene variation on expression.ResultsWe performed whole exome sequencing in 51 NOA patients and identified homozygous helicase for meiosis 1(HFM1) variants (NM_001017975: c.3490C > T: p.Q1164X; c.3470G > A: p.C1157Y) in two patients (3.9%, 2/51). Histopathology of the testis showed that spermatogenesis was completely blocked at metaphase in these two patients carrying the HFM1 homozygous variants. In comparison with unaffected controls, we found a significant reduction in the levels of HFM1 mRNA and protein expression in the testicular tissues from these two patients. The patients were also subjected to microTESE treatment, but the sperms could not be retrieved.ConclusionsThis study identified novel homozygous variants of HFM1 that are responsible for spermatogenic failure and NOA, and microTESE did not aid in retrieving sperms from these patients.

Dataset Information

Epigenetic Inactivation of SOX30 Is Associated with Male Infertility and Offers a Therapy Target for Non-obstructive Azoospermia.

Publications

Epigenetic Inactivation of SOX30 Is Associated with Male Infertility and Offers a Therapy Target for Non-obstructive Azoospermia.

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