Multiple LINEs of retrotransposon silencing mechanisms in the mammalian germline

Fang, Yang; Wang, P. Jeremy

doi:10.1016/j.semcdb.2016.03.001

Cited by 75 publications

(70 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). The second phase peaks in pachytene spermatocytes.…”

Section: Significancementioning

confidence: 99%

“…Afflicted males are invariably sterile because of spermatogenic failures. In addition, the majority of the mutants suffer meiotic arrest, accompanied by excessive DNA damage and numerous meiotic defects (12,13). A fundamental unanswered question in germ-cell biology is whether the elevated L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise.…”

Section: Significancementioning

confidence: 99%

“…A fundamental unanswered question in germ-cell biology is whether the elevated L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. One of the hypotheses is that loss of retrotransposon control at the transcriptional and posttranscriptional level would lead to massive insertional mutagenesis in developing germ cells, which would be subsequently eliminated through apoptosis (12,13). In principle, this hypothesis can be tested by measuring the level of new insertions in the piRNA pathway-deletion mutants.…”

Section: Significancementioning

confidence: 99%

“…Indeed, recent studies have uncovered an intricate network of defense mechanisms that mammalian germ cells use to control retrotransposon activities (12,13). Chief among them is the transcriptional and posttranscriptional silencing of retrotransposons by the PIWI-interacting RNA (piRNA) and DNA methylation pathway.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Intact piRNA pathway prevents L1 mobilization in male meiosis

Newkirk

Lee

Grandi

et al. 2017

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

View full text Add to dashboard Cite

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...

show abstract

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Intact piRNA pathway prevents L1 mobilization in male meiosis

Newkirk

Lee

Grandi

et al. 2017

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

View full text Add to dashboard Cite

show abstract

“…Loss of pre-pachytene piRNA biogenesis/loading onto Piwi proteins results in meiotic arrest at the zygotene stage of meiosis I [13, 16–23]. It is generally accepted that de-repression of TE causes massive DNA damage in spermatocytes, which activates the meiotic checkpoint and thus meiotic arrest in spermatocytes [24, 25]. …”

Section: Introductionmentioning

confidence: 99%

Mutations in the MOV10L1 ATP Hydrolysis Motif Cause piRNA Biogenesis Failure and Male Sterility in Mice

Pandey

Leu

et al. 2016

Biology of Reproduction

View full text Add to dashboard Cite

Piwi-interacting RNAs (piRNAs) are a class of small noncoding RNAs. piRNAs protect the genome integrity of the germline by silencing active transposable elements and are essential for germ cell development. Most piRNA pathway proteins are evolutionarily conserved. MOV10L1, a testis-specific RNA helicase, binds to piRNA precursors and is a master regulator of piRNA biogenesis in mouse. Here we report that mutation of the MOV10L1 ATP hydrolysis site leads to depletion of piRNAs on Piwi proteins, de-repression of transposable elements, and conglomeration of piRNA pathway proteins into polar granules. The Mov10l1 mutant mice exhibit meiotic arrest and male sterility. Our results show that mutation of the MOV10L1 ATP hydrolysis site perturbs piRNA biogenesis.

show abstract

An update on post‐transcriptional regulation of retrotransposons

Warkocki

2022

FEBS Letters

View full text Add to dashboard Cite

Retrotransposons, including LINE-1, Alu, SVA, and endogenous retroviruses, are one of the major constituents of human genomic repetitive sequences. Through the process of retrotransposition, some of them occasionally insert into new genomic locations by a copy-paste mechanism involving RNA intermediates. Irrespective of de novo genomic insertions, retrotransposon expression can lead to DNA double-strand breaks and stimulate cellular innate immunity through endogenous patterns. As a result, retrotransposons are tightly regulated by multi-layered regulatory processes to prevent the dangerous effects of their expression. In recent years, significant progress was made in revealing how retrotransposon biology intertwines with general posttranscriptional RNA metabolism. Here, I summarize current knowledge on the involvement of post-transcriptional factors in the biology of retrotransposons, focusing on LINE-1. I emphasize general RNA metabolisms such as methylation of adenine (m 6 A), RNA 3 0 -end polyadenylation and uridylation, RNA decay and translation regulation. I discuss the effects of retrotransposon RNP sequestration in cytoplasmic bodies and autophagy. Finally, I summarize how innate immunity restricts retrotransposons and how retrotransposons make use of cellular enzymes, including the DNA repair machinery, to complete their replication cycles.

show abstract

Multiple LINEs of retrotransposon silencing mechanisms in the mammalian germline

Cited by 75 publications

References 109 publications

Intact piRNA pathway prevents L1 mobilization in male meiosis

Intact piRNA pathway prevents L1 mobilization in male meiosis

Mutations in the MOV10L1 ATP Hydrolysis Motif Cause piRNA Biogenesis Failure and Male Sterility in Mice

An update on post‐transcriptional regulation of retrotransposons

Contact Info

Product

Resources

About