The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing

Vourekas, Anastassios; Zheng, Ke; Fu, Qi; Maragkakis, Manolis; Alexiou, Panagiotis; Ma, Jing; Pillai, Ramesh S.; Mourelatos, Zissimos P.; Wang, P. Jeremy

doi:10.1101/gad.254631.114

Cited by 149 publications

(220 citation statements)

References 77 publications

(138 reference statements)

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“…Mitochondriaanchored endonuclease PLD6/MITOPLD first cleaves piRNA precursor transcripts to produce the 5′ ends of piRNAs (Huang et al 2011, Watanabe et al 2011, Ipsaro et al 2012, Nishimasu et al 2012. MOV10L1, a testis-specific RNA helicase, supports the piRNA primary processing by recognizing and resolving secondary structures within the piRNA precursors (Zheng et al 2010, Vourekas et al 2015, Fu et al 2016). piRNA intermediate transcripts are then loaded on PIWI proteins that stabilize their 5′ ends.…”

Section: Germ Granules As Platforms For Pirna Pathwaymentioning

confidence: 99%

Germ granule-mediated RNA regulation in male germ cells

Lehtiniemi

Kotaja

2018

Reproduction

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Germ cells have exceptionally diverse transcriptomes. Furthermore, the progress of spermatogenesis is accompanied by dramatic changes in gene expression patterns, the most drastic of them being near-to-complete transcriptional silencing during the final steps of differentiation. Therefore, accurate RNA regulatory mechanisms are critical for normal spermatogenesis. Cytoplasmic germ cell-specific ribonucleoprotein (RNP) granules, known as germ granules, participate in posttranscriptional regulation in developing male germ cells. Particularly, germ granules provide platforms for the PIWI-interacting RNA (piRNA) pathway and appear to be involved both in piRNA biogenesis and piRNA-targeted RNA degradation. Recently, other RNA regulatory mechanisms, such as the nonsense-mediated mRNA decay pathway have also been associated to germ granules providing new exciting insights into the function of germ granules. In this review article, we will summarize our current knowledge on the role of germ granules in the control of mammalian male germ cell's transcriptome and in the maintenance of fertility.Reproduction (2018) 155 R77-R91

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Section: Germ Granules As Platforms For Pirna Pathwaymentioning

confidence: 99%

Germ granule-mediated RNA regulation in male germ cells

Lehtiniemi

Kotaja

2018

Reproduction

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“…To test whether our 5′UTR-ORFeus transgene was regulated by the fetal piRNA pathway, we introduced the transgene into a Mov10l1-deficient genetic background (41). MOV10L1 is an RNA helicase essential for primary piRNA biogenesis (42). Global deletion of Mov10l1 leads to the loss of fetal piRNAs and malespecific meiotic defects, which are accompanied by L1 hypomethylation and up-regulation at both RNA and protein levels in postnatal Mov10l1 −/− testes (41,43).…”

Section: Developing An L1 Transgene Regulated By the Endogenous Mouse L1mentioning

confidence: 99%

Intact piRNA pathway prevents L1 mobilization in male meiosis

Newkirk

Lee

Grandi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter. Importantly, DNA methylation dynamics of a single-copy transgene were indistinguishable from those of endogenous L1s. Analysis of Mov10l1 −/− testes established that de novo methylation of the L1 transgene required the intact piRNA pathway. Consistent with loss of DNA methylation and programmed reduction of H3K9me2 at meiotic onset, the transgene showed 1,400-fold increase in RNA expression and consequently 70-fold increase in retrotransposition in postnatal day 14 Mov10l1 −/− germ cells compared with the wildtype. Analysis of adult Mov10l1 −/− germ-cell fractions indicated a stage-specific increase of retrotransposition in the early meiotic prophase. However, extrapolation of the transgene data to endogenous L1s suggests that it is unlikely insertional mutagenesis alone accounts for the Mov10l1 −/− phenotype. Indeed, pharmacological inhibition of reverse transcription did not rescue the meiotic defect. Cumulatively, these results establish the occurrence of productive L1 mobilization in the absence of an intact piRNA pathway but leave open the possibility of processes preceding L1 integration in triggering meiotic checkpoints and germ-cell death. Additionally, our data suggest that many heritable L1 insertions originate from individuals with partially compromised piRNA defense.LINE-1 reporter transgene | meiotic arrest | PIWI-interacting RNA | retrotransposition | spermatogenesis T he bulk of mammalian genomes are made up of transposable elements, the majority of which are retrotransposons (1). Retrotransposons are classified into long-interspersed elements (LINEs), short-interspersed elements (SINEs), and LTR retrotransposons, which collectively account for 43% and 37% of the human and mouse genomes, respectively (2). Retrotransposons amplify in the genome through an RNA intermediate, a process termed retrotransposition. LINEs are autonomous elements. An intact, full-length LINE-1 (L1) encodes two ORFs (i.e., ORF1 and ORF2); both are required for L1 mobilization (3). SINEs are nonautonomous elements and rely on L1's proteins for propagation in the genome (4). LTR retrotransposons are autonomous but appear to be inactivated in the human genome (5). Retrotransposition endangers the integrity of both somatic and germline genomes through insertional mutagenesis. In somatic tissues, both elevated L1 expression and retrotransposition have been strongly associated with many types of human cancers (6, 7). In a few cases, specific retrotransposition events (i.e., insertions) have been determined to drive t...

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“…Piwi proteins are expressed primarily in the germline, bind piRNAs and use them to target and silence transposons (Seto et al 2007;Klattenhoff and Theurkauf 2008;Ghildiyal and Zamore 2009;Senti and Brennecke 2010;Castaneda et al 2011;Siomi et al 2011;Ishizu et al 2012;Pillai and Chuma 2012;Guzzardo et al 2013;Weick and Miska 2014). CLIP-seq for Piwi proteins revealed that they may also bind directly to long RNAs without using piRNAs as guides, either in the process of piRNA biogenesis or to bind to mRNAs (Vourekas et al 2012(Vourekas et al , 2015.…”

Section: Introductionmentioning

confidence: 99%

“…Evidently, identifying binding sites is an important task but it also has a quite limited analysis scope. In the general case, a CLIP-seq experiment can reveal positional information for RBP sites but it can also reveal structural and mechanistic insight for the bound protein/RNA complexes (Huelga et al 2012;Vourekas et al 2012Vourekas et al , 2015Weyn-Vanhentenryck et al 2014). Moreover, RBP function might differ depending on the genomic context, and a generic CLIP-seq analysis tool has to provide a straightforward mechanism to analyze data sets under different criteria and parameters.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to RNA-seq, for which there are well-defined analysis outputs and several established tools (Katz et al 2010;Anders et al 2013), CLIP-seq usually involves analyses that are inherently nuanced and, more often than not, widely diverse (Chi et al 2009;Cho et al 2012;Huelga et al 2012;Vourekas et al 2012Vourekas et al , 2015Ibrahim et al 2013;Nakaya et al 2013;Chu et al 2015). CLIP-seq analyses usually start with a series of well-defined processing steps such as adaptor trimming and alignment of the sequenced reads on a reference genome.…”

Section: Introductionmentioning

confidence: 99%

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CLIPSeqTools—a novel bioinformatics CLIP-seq analysis suite

Maragkakis

Alexiou

Nakaya

et al. 2015

RNA

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Immunoprecipitation of RNA binding proteins (RBPs) after in vivo crosslinking, coupled with sequencing of associated RNA footprints (HITS-CLIP, CLIP-seq), is a method of choice for the identification of RNA targets and binding sites for RBPs. Compared with RNA-seq, CLIP-seq analysis is widely diverse and depending on the RBPs that are analyzed, the approaches vary significantly, necessitating the development of flexible and efficient informatics tools. In this study, we present CLIPSeqTools, a novel, highly flexible computational suite that can perform analysis from raw sequencing data with minimal user input. It contains a wide array of tools to provide an in-depth view of CLIP-seq data sets. It supports extensive customization and promotes improvization, a critical virtue, since CLIP-seq analysis is rarely well defined a priori. To highlight CLIPSeqTools capabilities, we used the suite to analyze Ago-miRNA HITS-CLIP data sets that we prepared from human brains.

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The RNA helicase MOV10L1 binds piRNA precursors to initiate piRNA processing

Cited by 149 publications

References 77 publications

Germ granule-mediated RNA regulation in male germ cells

Germ granule-mediated RNA regulation in male germ cells

Intact piRNA pathway prevents L1 mobilization in male meiosis

CLIPSeqTools—a novel bioinformatics CLIP-seq analysis suite

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