A team of scientists led by Dr. LIU Mofang at the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, and Dr. SHI Huijuan at Shanghai Institute of Planned Parenthood Research, Fudan University Reproduction and Development Institution, have found that Ubiquitination-deficient mutations in human Piwi (Hiwi) gene cause male infertility. This work entitled “Ubiquitination-deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis” was online published in Cell on May 25, 2017. The work was collaborated with Drs. FU Xiangdong, LI Zheng, LI Dangsheng, LI Jinsong, and WU Ligang.
The evolutionarily conserved Piwi proteins belong to the Piwi clade of the Argonaute family, each of which is specifically expressed during the development of animal germline.Piwi proteins are known to enlist germline-specific Piwi-interacting RNAs (piRNAs) to suppress transposable elements and protect the integrity of the genome in germ cells. Extensive genetic studies in worms, flies, fish and mice indicate that Piwi proteins are essential for gametogenesis in animals. The human genome encodes four Piwi family members, including Hiwi, Hili, Hiwi2 and Piwil3, all of which are mainly expressed in testis, but their potential function in human germline development has remained elusive. Despite the identification of several single nucleotide polymorphisms (SNPs) in human Piwi genes, whether Piwi is an actual disease gene in human infertility remains unknown.
GOU Lantao, KANG Junyan, DAI Peng, WANG Xin, LI Feng and their colleagues, under the supervision of Drs. LIU Mofang and SHI Huijuan, identified the ubiquination-resistant mutations in Hiwi gene in patients with azoospermia. By modeling such mutations in both knock-in and transgenic mice, they demonstrate that D-box mutations impeded MIWI degradation and contribute to male infertility. Mechanistically, MIWI binds the histone ubiquitin ligase RNF8 in a piRNA-independent manner and that MIWI stabilization sequesters RNF8 in the cytoplasm of late spermatids. The resulting aberrant sperm show histone retention, abnormal morphology and severely compromised activity, which can be functionally rescued via blocking RNF8-MIWI interaction in spermatidswith an RNF8-N peptide. Thus, this work identifies a role for Piwi function in human genetics and reveals mechanism for regulated packaging of genomic DNA into functional sperm.
This study was supported by the grants from the Chinese Academy of Sciences, National Natural Science Foundation of China, Ministry of Science and Technology, and Science and Technology Commission of Shanghai Municipality.
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