Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis

Gou, Lantu; Kang, Jun-Yan; Dai, Peng; Wang, Xin; Li, Feng; Zhao, Shuang; Zhang, Man; Hua, Min-Min; Lü, Yi; Zhu, Yong; Zheng, Li; Chen, H; Wu, Ligang; Li, Dangsheng; Fu, Xiang‐Dong; Li, Jinsong; Shi, Huijuan; Lin, Li

doi:10.1016/j.cell.2017.04.034

Cited by 211 publications

(122 citation statements)

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“…IMC components play multiple distinct roles through interplay with other nuage proteins, including piRNA biogenesis pathway, mRNA storage, export and translation, alternative splicing, and DNA damage ( Figure 1B). Importantly, germline mutations of several IMC components were identified in human patients with oligoasthenoteratozoospermia/azoospermia, such as PIWI (MIWI), DDX25, TDRD6, and MITOPLD [94]. In conclusion, the normal physical function of IMC and the communication between IMC and piP-body are essential for the sustainment of spermatogenesis.…”

Section: Ping-pong Amplification Cyclementioning

confidence: 95%

Mitochondria Associated Germinal Structures in Spermatogenesis: piRNA Pathway Regulation and Beyond

Wang

Guo

et al. 2020

Cells

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Multiple specific granular structures are present in the cytoplasm of germ cells, termed nuage, which are electron-dense, non-membranous, close to mitochondria and/or nuclei, variant size yielding to different compartments harboring different components, including intermitochondrial cement (IMC), piP-body, and chromatoid body (CB). Since mitochondria exhibit different morphology and topographical arrangements to accommodate specific needs during spermatogenesis, the distribution of mitochondria-associated nuage is also dynamic. The most relevant nuage structure with mitochondria is IMC, also called pi-body, present in prospermatogonia, spermatogonia, and spermatocytes. IMC is primarily enriched with various Piwi-interacting RNA (piRNA) proteins and mainly functions as piRNA biogenesis, transposon silencing, mRNA translation, and mitochondria fusion. Importantly, our previous work reported that mitochondria-associated ER membranes (MAMs) are abundant in spermatogenic cells and contain many crucial proteins associated with the piRNA pathway. Provocatively, IMC functionally communicates with other nuage structures, such as piP-body, to perform its complex functions in spermatogenesis. Although little is known about the formation of both IMC and MAMs, its distinctive characters have attracted considerable attention. Here, we review the insights gained from studying the structural components of mitochondria-associated germinal structures, including IMC, CB, and MAMs, which are pivotal structures to ensure genome integrity and male fertility. We discuss the roles of the structural components in spermatogenesis and piRNA biogenesis, which provide new insights into mitochondria-associated germinal structures in germ cell development and male reproduction. Cells 2020, 9, 399 2 of 20Mitochondria-associated ER membranes (MAMs) are tight structural contacts, also named as MERCs (mitochondria-ER contacts);~20% of the mitochondrial surface are jointly opposing and contact directly with the ER, yielding to approximately 10 and 30 nm in distance [4,5]. MAMs participate in several cellular signaling pathways, including calcium transmission, phospholipid exchange, intracellular trafficking, autophagy, ER stress, mitochondrial biogenesis, and inflammasome formation. Disturbances to MAMs lead to neurodegenerative diseases and cancer [6,7]. Our previous work reported that MAMs are abundant in both human and mouse spermatogenic cells, and contain many crucial proteins that are associated with the Piwi-interacting RNA (piRNA) pathway [8]. However, the functions of MAMs are still mysterious in spermatogenesis.In this review, we review the insights gained from studying the structural components of mitochondria-associated germinal structures, including IMC, CB, and MAMs, which are pivotal structures to ensure genome integrity and male fertility. We summarize the ultra-structure of IMC and MAMs in mouse spermatocyte, as shown in Figure 1A. We also discuss the roles of the structural components in piRNA biogenesis and propose that further s...

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Section: Ping-pong Amplification Cyclementioning

confidence: 95%

Mitochondria Associated Germinal Structures in Spermatogenesis: piRNA Pathway Regulation and Beyond

Wang

Guo

et al. 2020

Cells

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“…Germline transposon silencing is mediated by small PIWI interacting RNAs (piRNAs), which are bound by PIWI proteins and direct post-transcriptional and transcriptional silencing of target transposons (Brennecke et al, 2007; Gunawardane et al, 2007; Iwasaki et al, 2015; Kuramochi-Miyagawa et al, 2008; Sienski et al, 2012). Mutations that disrupt the piRNA pathway lead to sterility and transposon mobilization in worms, flies, fish and mice, and have been linked to human infertility (Batista et al, 2008; Carmell et al, 2007; Das et al, 2008; Gou et al, 2017; Gu et al, 2010; Heyn et al, 2012; Houwing et al, 2008; Lin and Spradling, 1997; Weick and Miska, 2014). In striking contrast, genes with essential functions in piRNA production and transposon silencing in established model systems are often very poorly conserved, and piRNA biogenesis and sequence composition show remarkable phylogenetic diversity (Chirn et al, 2015; Obbard et al, 2009; Simkin et al, 2013; Yi et al, 2014; Zanni et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Adaptive Evolution Leads to Cross-Species Incompatibility in the piRNA Transposon Silencing Machinery

et al. 2017

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SUMMARY Reproductive isolation defines species divergence and is linked to adaptive evolution of hybrid incompatibility genes. Hybrids between Drosophila melanogaster and Drosophila simulans are sterile and phenocopy mutations in the piRNA pathway, which silences transposons and shows pervasive adaptive evolution, and Drosophila rhino and deadlock encode rapidly evolving components of a complex that binds to piRNA clusters. We show that Rhino and Deadlock interact and co-localize in simulans and melanogaster, but simulans Rhino does not bind melanogaster Deadlock, due to substitutions in the rapidly evolving Shadow domain. Significantly, a chimera expressing the simulans Shadow domain in a melanogaster Rhino backbone fails to support piRNA production, disrupts binding to piRNA clusters, and leads to ectopic localization to bulk heterochromatin. Fusing melanogaster Deadlock to simulans Rhino, by contrast, restores localization to clusters. Deadlock binding thus directs Rhino to piRNA clusters, and Rhino-Deadlock co-evolution has produced cross-species incompatibilities, which may contribute to reproductive isolation.

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“…Even though piRNA metabolic process was reported to be enriched among NOA-down-regulated genes in an integrated analysis of miRNAs and mRNAs (45), other transcriptomic analysis did not report piRNA metabolic process and ubiquitination, which were enriched among down-regulated genes in the current study. But, germline mutations in the human Piwi gene in patients with azoospermia have been reported to prevent the ubiquitination and degradation of the corresponding protein (46). Global ubiquitination of H2A and H2B mediated by the Piwi-dependent RNF8 protein seems to be a key step in histone to protamine transition (47).…”

Section: Discussionmentioning

confidence: 99%

Listing candidate diagnostic markers and transcriptomic exploration of the molecular basis of a type of male infertility (Non-Obstructive Azoospermia), via next generation sequencing methods

Govindkumar

Basavaraju

Bajpai³

et al. 2019

Preprint

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Studying the molecular basis of Non-Obstructive Azoospermia (NOA), a type of male infertility with failed spermatogenesis at various stages, can also help in exploring molecular basis of human spermatogenesis and possibly pave way to identify new targets for male contraceptive development. Hence, we initiated a functional genomics study by applying RNA-seq. Testicular biopsies collected from donors with Non-Obstructive Azoospermia (NOA), Obstructive Azoospermia (OA), Congenital Bilateral Absence of the Vas Deferens (CBAVD), and Varicocele (VA) conditions. Strong association of 100+ genes with human spermatogenesis and NOA has been detected via NGS-based transcriptomic analysis. In addition, 20 RNA molecules have been short-listed for potential diagnostic applications (non-obstructive azoospermia vs. obstructive azoospermia, varicocele or normal). A hierarchical list of several genes and alternatively spliced mRNAs, transcribed differentially in NOA, is reported -based on a 'strength of association'. Such association with NOA, spermatogenesis or both is a new finding for many genes as revealed by a comparison with a newly prepared comprehensive list of genes having such association with human spermatogenesis/NOA. Many top-ranking genes involved in viral gene expression were up-regulated in testes from NOA-patients, while those associated with an antiviral mechanism were down-regulated. A tangential finding: while most well-established control mRNAs did not qualify, two new ones worked best in RT-qPCR experiments. Needle-aspiration of testicular biopsies, followed by the use of short-listed promising candidate biomarkers (i.e., 16 mRNA & 4 chimeric transcripts) and control mRNAs in RT-qPCR-based diagnostic assays, may help to avoid open surgeries in future.

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Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis

Cited by 211 publications

References 49 publications

Mitochondria Associated Germinal Structures in Spermatogenesis: piRNA Pathway Regulation and Beyond

Mitochondria Associated Germinal Structures in Spermatogenesis: piRNA Pathway Regulation and Beyond

Adaptive Evolution Leads to Cross-Species Incompatibility in the piRNA Transposon Silencing Machinery

Listing candidate diagnostic markers and transcriptomic exploration of the molecular basis of a type of male infertility (Non-Obstructive Azoospermia), via next generation sequencing methods

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