piRNA pathway targets active LINE1 elements to establish the repressive H3K9me3 mark in germ cells

Pezić, Dubravka; Manakov, Sergei A.; Sachidanandam, Ravi; Aravin, Alexei A.

doi:10.1101/gad.240895.114

Cited by 198 publications

(188 citation statements)

References 59 publications

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“…While this paper was under review, Aravin and colleagues (Pezic et al 2014) showed that deletion of Miwi2 led to a decrease in H3K9me3 levels and derepression specifically of young L1Md elements in P10 male germ cells. Taken together with the data presented here, these results indicate that the piRNA pathway may be required to maintain SETDB1-deposited H3K9me3 at young LINE1 elements or for deposition of H3K9me3 at previously unmarked elements at later stages of premeiotic spermatogenesis.…”

Section: Addendummentioning

confidence: 99%

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

et al. 2014

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Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at approximately embryonic day 15.5 (E15.5) in prospermatogonia. Earlier in germline development, the genome, including most retrotransposons, is progressively demethylated. Young ERVK and ERV1 elements, however, retain intermediate methylation levels. As DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes, we determined whether retrotransposons are marked by H3K9me3 and H3K27me3 using a recently developed low-input ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) method. Although these repressive histone modifications are found predominantly on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated long terminal repeats (LTRs) and LINE1 elements. Germline-specific conditional knockout of the H3K9 methyltransferase SETDB1 yields a decrease of both marks and DNA methylation at H3K9me3-enriched retrotransposon families. Strikingly, Setdb1 knockout E13.5 PGCs show concomitant derepression of many marked ERVs, including intracisternal A particle (IAP), ETn, and ERVK10C elements, and ERV-proximal genes, a subset in a sex-dependent manner. Furthermore, Setdb1 deficiency is associated with a reduced number of male E13.5 PGCs and postnatal hypogonadism in both sexes. Taken together, these observations reveal that SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline.

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Section: Addendummentioning

confidence: 99%

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

et al. 2014

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“…retrotransposon-derived piRNAs serve as a guide to selectively target young L1 families for de novo DNA methylation (16) or H3K9me3 modification (17). Functional deletion of many cofactors in the piRNA-DNA methylation pathway leads to abnormal L1 expression accompanied by the loss of DNA methylation at L1 promoters (12,13).…”

Section: Significancementioning

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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“…20 piRNA is a kind of single-strand small noncoding RNA transcribed from genomic loci containing repetitive elements that binds to Piwi proteins to form a complex that suppresses L1 proliferation via RNA degradation, 21 DNA methylation, 22 or histone modification. 23 Apart from siRNA and piRNA, other defensive strategies , and a 3′ UTR ending with a poly(A) tail. Its 5′ UTR harbors two internal promoters: one is sense and the other is antisense.…”

Section: Structure and Retrotransposition Process Of L1mentioning

confidence: 99%

LINE-1 in cancer: multifaceted functions and potential clinical implications

Han

et al. 2016

Genetics in Medicine

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ReviewThe human genome is abundant with interspersed repetitive sequences originated from retrotransposons. Until now, three categories of retrotransposons have remained unequivocally active: LINE-1(L1), Alu, and SVA elements. The first one is autonomous-capable of self-propagation through RNA intermediates-and the latter two are nonautonomous and thus rely on L1 for mobilization. There are approximately 500,000 L1 copies in the human genome, composing 17% of human DNA.

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piRNA pathway targets active LINE1 elements to establish the repressive H3K9me3 mark in germ cells

Cited by 198 publications

References 59 publications

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

Intact piRNA pathway prevents L1 mobilization in male meiosis

LINE-1 in cancer: multifaceted functions and potential clinical implications

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