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Mouse MOV10L1 associates with Piwi proteins and is an essential component of the Piwi-interacting RNA (piRNA) pathway.

ABSTRACT: Piwi-interacting RNAs (piRNAs) are essential for silencing of transposable elements in the germline, but their biogenesis is poorly understood. Here we demonstrate that MOV10L1, a germ cell-specific putative RNA helicase, is associated with Piwi proteins. Genetic disruption of the MOV10L1 RNA helicase domain in mice renders both MILI and MIWI2 devoid of piRNAs. Absence of a functional piRNA pathway in Mov10l1 mutant testes causes loss of DNA methylation and subsequent derepression of retrotransposons in germ cells. The Mov10l1 mutant males are sterile owing to complete meiotic arrest. This mouse mutant expresses Piwi proteins but lacks piRNAs, suggesting that MOV10L1 is required for piRNA biogenesis and/or loading to Piwi proteins.

SUBMITTER: Zheng K

PROVIDER: S-EPMC2900664 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Mouse MOV10L1 associates with Piwi proteins and is an essential component of the Piwi-interacting RNA (piRNA) pathway.

Zheng Ke K Xiol Jordi J Reuter Michael M Eckardt Sigrid S Leu N Adrian NA McLaughlin K John KJ Stark Alexander A Sachidanandam Ravi R Pillai Ramesh S RS Wang Peijing Jeremy PJ

Proceedings of the National Academy of Sciences of the United States of America 20100601 26

Piwi-interacting RNAs (piRNAs) are essential for silencing of transposable elements in the germline, but their biogenesis is poorly understood. Here we demonstrate that MOV10L1, a germ cell-specific putative RNA helicase, is associated with Piwi proteins. Genetic disruption of the MOV10L1 RNA helicase domain in mice renders both MILI and MIWI2 devoid of piRNAs. Absence of a functional piRNA pathway in Mov10l1 mutant testes causes loss of DNA methylation and subsequent derepression of retrotransp ...[more]

PMID: 20534472

Similar Datasets

Mouse MOV10L1 associates with Piwi proteins and is an essential component of the piRNA pathway

Project description:Piwi-interacting RNAs (piRNAs) are essential for silencing of transposable elements in the germline but their biogenesis is poorly understood. Here we demonstrate that MOV10L1, a germ cell-specific putative RNA helicase, is associated with Piwi proteins. Genetic disruption of the MOV10L1 RNA helicase domain in mice renders both MILI and MIWI2 devoid of piRNAs. Absence of a functional piRNA pathway in Mov10l1 mutant testes causes loss of DNA methylation and subsequent de-repression of retrotransposons in germ cells. The Mov10l1 mutant males are sterile due to complete meiotic arrest. This is the first mouse mutant that expresses Piwi proteins but lacks piRNAs, suggesting that MOV10L1 is required for piRNA biogenesis and/or loading to Piwi proteins.

2010-06-13 | GSE21763 | GEO

Mouse MOV10L1 associates with Piwi proteins and is an essential component of the piRNA pathway

2010-06-12 | E-GEOD-21763 | biostudies-arrayexpress

MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs.

Project description:Piwi-interacting RNAs (piRNAs) comprise a broad class of small noncoding RNAs that function as an endogenous defense system against transposable elements. Here we show that the putative DExD-box helicase MOV10-like-1 (MOV10L1) is essential for silencing retrotransposons in the mouse male germline. Mov10l1 is specifically expressed in germ cells with increasing expression from gonocytes/type A spermatogonia to pachytene spermatocytes. Primary spermatocytes of Mov10l1(-/-) mice show activation of LTR and LINE-1 retrotransposons, followed by cell death, causing male infertility and a complete block of spermatogenesis at early prophase of meiosis I. Despite the early expression of Mov10l1, germline stem cell maintenance appears unaffected in Mov10l1(-/-) mice. MOV10L1 interacts with the Piwi proteins MILI and MIWI. MOV10L1 also interacts with heat shock 70-kDa protein 2 (HSPA2), a testis-enriched chaperone expressed in pachytene spermatocytes and also essential for male fertility. These studies reveal a crucial role of MOV10L1 in male fertility and piRNA-directed retrotransposon silencing in male germ cells and suggest that MOV10L1 functions as a key component of a safeguard mechanism for the genetic information in male germ cells of mammals.

| S-EPMC2900665 | biostudies-literature

The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing.

Project description:Piwi-piRNA (Piwi-interacting RNA) ribonucleoproteins (piRNPs) enforce retrotransposon silencing, a function critical for preserving the genome integrity of germ cells. The molecular functions of most of the factors that have been genetically implicated in primary piRNA biogenesis are still elusive. Here we show that MOV10L1 exhibits 5'-to-3' directional RNA-unwinding activity in vitro and that a point mutation that abolishes this activity causes a failure in primary piRNA biogenesis in vivo. We demonstrate that MOV10L1 selectively binds piRNA precursor transcripts and is essential for the generation of intermediate piRNA processing fragments that are subsequently loaded to Piwi proteins. Multiple analyses suggest an intimate coupling of piRNA precursor processing with elements of local secondary structures such as G quadruplexes. Our results support a model in which MOV10L1 RNA helicase activity promotes unwinding and funneling of the single-stranded piRNA precursor transcripts to the endonuclease that catalyzes the first cleavage step of piRNA processing.

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Piwi-interacting RNA (piRNA) expression patterns in pearl oyster (Pinctada fucata) somatic tissues.

Project description:Piwi-interacting RNAs (piRNAs) belong to a recently discovered class of small non-coding RNAs whose best-understood function is repressing transposable element activity. Most piRNA studies have been conducted on model organisms and little is known about piRNA expression and function in mollusks. We performed high-throughput sequencing of small RNAs extracted from the mantle, adductor muscle, gill, and ovary tissues of the pearl oyster, Pinctada fucata. RNA species with sequences of approximately 30 nt were widely expressed in all tissues. Uridine at the 5' terminal and protection from β-elimination at the 3' terminal suggested that these were putative piRNAs. A total of 18.0 million putative piRNAs were assigned to 2.8 million unique piRNAs, and 35,848 piRNA clusters were identified. Mapping to the reference genome showed that 25% of the unique piRNAs mapped to multiple tandem loci on the scaffold. Expression patterns of the piRNA clusters were similar within the somatic tissues, but differed significantly between the somatic and gonadal tissues. These findings suggest that in pearl oysters piRNAs have important and novel functions beyond those in the germ line.

| S-EPMC6342924 | biostudies-literature

Uniting germline and stem cells: the function of Piwi proteins and the piRNA pathway in diverse organisms.

Project description:The topipotency of the germline is the full manifestation of the pluri- and multipotency of embryonic and adult stem cells, thus the germline and stem cells must share common mechanisms that guarantee their multipotentials in development. One of the few such known shared mechanisms is represented by Piwi proteins, which constitute one of the two subfamilies of the Argonaute protein family. Piwi proteins bind to Piwi-interacting RNAs (piRNAs) that are generally 26 to 31 nucleotides in length. Both Piwi proteins and piRNAs are most abundantly expressed in the germline. Moreover, Piwi proteins are expressed broadly in certain types of somatic stem/progenitor cells and other somatic cells across animal phylogeny. Recent studies indicate that the Piwi-piRNA pathway mediates epigenetic programming and posttranscriptional regulation, which may be responsible for its function in germline specification, gametogenesis, stem cell maintenance, transposon silencing, and genome integrity in diverse organisms.

| S-EPMC3832951 | biostudies-literature

PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells.

Project description:PIWI proteins and their bound PIWI-interacting RNAs (piRNAs) are found in animal germlines and are essential for fertility, but their functions outside of the gonad are not well understood. The cnidarian Hydra is a simple metazoan with well-characterized stem/progenitor cells that provides a unique model for analysis of PIWI function. Here we report that Hydra has two PIWI proteins, Hydra PIWI (Hywi) and Hydra PIWI-like (Hyli), both of which are expressed in all Hydra stem/progenitor cells, but not in terminally differentiated cells. We identified ∼15 million piRNAs associated with Hywi and/or Hyli and found that they exhibit the ping-pong signature of piRNA biogenesis. Hydra PIWI proteins are strictly cytoplasmic and thus likely act as posttranscriptional regulators. To explore this function, we generated a Hydra transcriptome for piRNA mapping. piRNAs map to transposons with a 25- to 35-fold enrichment compared with the abundance of transposon transcripts. By sequencing the small RNAs specific to the interstitial, ectodermal, and endodermal lineages, we found that the targeting of transposons appears to be largely restricted to the interstitial lineage. We also identified putative nontransposon targets of the pathway unique to each lineage. Finally we demonstrate that hywi function is essential in the somatic epithelial lineages. This comprehensive analysis of the PIWI-piRNA pathway in the somatic stem/progenitor cells of a nonbilaterian animal suggests that this pathway originated with broader stem cell functionality.

| S-EPMC3890812 | biostudies-literature

PIWI Slicing and EXD1 Drive Biogenesis of Nuclear piRNAs from Cytosolic Targets of the Mouse piRNA Pathway.

Project description:PIWI-interacting RNAs (piRNAs) guide PIWI proteins to suppress transposons in the cytoplasm and nucleus of animal germ cells, but how silencing in the two compartments is coordinated is not known. Here we demonstrate that endonucleolytic slicing of a transcript by the cytosolic mouse PIWI protein MILI acts as a trigger to initiate its further 5'→3' processing into non-overlapping fragments. These fragments accumulate as new piRNAs within both cytosolic MILI and the nuclear MIWI2. We also identify Exonuclease domain-containing 1 (EXD1) as a partner of the MIWI2 piRNA biogenesis factor TDRD12. EXD1 homodimers are inactive as a nuclease but function as an RNA adaptor within a PET (PIWI-EXD1-Tdrd12) complex. Loss of Exd1 reduces sequences generated by MILI slicing, impacts biogenesis of MIWI2 piRNAs, and de-represses LINE1 retrotransposons. Thus, piRNA biogenesis triggered by PIWI slicing, and promoted by EXD1, ensures that the same guides instruct PIWI proteins in the nucleus and cytoplasm.

| S-EPMC4712191 | biostudies-literature

Biopathological Significance of PIWI-piRNA Pathway Deregulation in Invasive Breast Carcinomas.

Project description:The PIWI proteins emerging in the development of human cancers, edify PIWI-piRNA ribonucleoproteic complexes acting as pivotal regulators of genome integrity, differentiation and homeostasis. The aim of this study is to analyze the four PIWILs gene expression in invasive breast carcinomas (IBCs): at RNA level using quantitative RT-PCR (n = 526) and protein level using immunohistochemistry (n = 150). In normal breast tissue, PIWILs 2 and 4 were solely expressed, whereas an abnormal emergence of PIWIL1 and 3 was observed in respectively 30% and 6% of IBCs. Conversely, PIWIL2 was underexpressed in 48.3% and PIWIL4 downregulated in 43.3% of IBCs. Significant positive associations were observed between PIWIL4 underexpression, HR+ status and HR+ ERBB2+ molecular subtype and PIWIL2 underexpression, PR- status, ERBB2- status and molecular subtype. Similar patterns of PIWIL deregulation were observed in a multitumoral panel, suggesting a generic mechanism in most cancers. PIWIL2-4 underexpression was mainly regulated at epigenetic or post-transcriptional levels. PIWIL2 underexpression was significantly associated with DNA methylation and strong cytotoxic immune response. PIWIL2-4 were mainly associated with genes implicated in cell proliferation. As a result of this study, characterization of the PIWIL-piRNA pathway in IBCs opens interesting therapeutic perspectives using piRNAs, hypomethylating drugs, checkpoints immunotherapies and anti-PIWIL 1-3 antibodies.

| S-EPMC7600338 | biostudies-literature

2L-piRNA: A Two-Layer Ensemble Classifier for Identifying Piwi-Interacting RNAs and Their Function.

Project description:Involved with important cellular or gene functions and implicated with many kinds of cancers, piRNAs, or piwi-interacting RNAs, are of small non-coding RNA with around 19-33 nt in length. Given a small non-coding RNA molecule, can we predict whether it is of piRNA according to its sequence information alone? Furthermore, there are two types of piRNA: one has the function of instructing target mRNA deadenylation, and the other does not. Can we discriminate one from the other? With the avalanche of RNA sequences emerging in the postgenomic age, it is urgent to address the two problems for both basic research and drug development. Unfortunately, to the best of our knowledge, so far no computational methods whatsoever could be used to deal with the second problem, let alone deal with the two problems together. Here, by incorporating the physicochemical properties of nucleotides into the pseudo K-tuple nucleotide composition (PseKNC), we proposed a powerful predictor called 2L-piRNA. It is a two-layer ensemble classifier, in which the first layer is for identifying whether a query RNA molecule is piRNA or non-piRNA, and the second layer for identifying whether a piRNA is with or without the function of instructing target mRNA deadenylation. Rigorous cross-validations have indicated that the success rates achieved by the proposed predictor are quite high. For the convenience of most biologists and drug development scientists, the web server for 2L-piRNA has been established at http://bioinformatics.hitsz.edu.cn/2L-piRNA/, by which users can easily get their desired results without the need to go through the mathematical details.

| S-EPMC5415553 | biostudies-literature

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