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Restriction of LINE1 activity by RNAi correlates with mouse ES cell differentiation

ABSTRACT: Long interspersed elements 1 (LINE-1 or L1) are retrotransposons that dominate the mouse genomic landscape, and are expressed in Embryonic Stem Cells (ESCs), germ cells, and during early development. Based on clear precedents in plants and fission yeast, we investigated in this study a role for RNAi and other RNA degradation pathways in the regulation of L1 expression and mobilization. We uncovered the existence of novel small (s)RNAs that map to active L1 elements. Some of these sRNAs have characteristics of cognate short-interfering RNA populations, while others display length heterogeneity that evokes a biogenesis through a RNA surveillance pathway, in a Dicer-independent manner. We additionally found that genetic ablation of Dicer and the sRNA effector protein AGO2 has complex and profound consequences on L1 transcription and mobilization in ESCs, indicating that endogenous RNA interference (RNAi) pathway indeed maintain genomic integrity against L1 proliferation. Finally, we investigated the implication of L1 retrotransposition during ESC differentiation and propose that the mobilization of L1 elements in Dicer mutant ESCs could partially explain the inability of these cells to differentiate.

ORGANISM(S): Mus musculus

PROVIDER: GSE43110 | GEO | 2013/12/11

SECONDARY ACCESSION(S): PRJNA184582

REPOSITORIES: GEO

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Restriction of LINE1 activity by RNAi correlates with mouse ES cell differentiation

Project description:Long interspersed elements 1 (LINE-1 or L1) are retrotransposons that dominate the mouse genomic landscape, and are expressed in Embryonic Stem Cells (ESCs), germ cells, and during early development. Based on clear precedents in plants and fission yeast, we investigated in this study a role for RNAi and other RNA degradation pathways in the regulation of L1 expression and mobilization. We uncovered the existence of novel small (s)RNAs that map to active L1 elements. Some of these sRNAs have characteristics of cognate short-interfering RNA populations, while others display length heterogeneity that evokes a biogenesis through a RNA surveillance pathway, in a Dicer-independent manner. We additionally found that genetic ablation of Dicer and the sRNA effector protein AGO2 has complex and profound consequences on L1 transcription and mobilization in ESCs, indicating that endogenous RNA interference (RNAi) pathway indeed maintain genomic integrity against L1 proliferation. Finally, we investigated the implication of L1 retrotransposition during ESC differentiation and propose that the mobilization of L1 elements in Dicer mutant ESCs could partially explain the inability of these cells to differentiate. 2 samples examined: WT E14 and Dicer mutant mouse ESCs

2013-12-11 | E-GEOD-43110 | biostudies-arrayexpress

Massive LINE1 retrotransposon Invasion in Tuberous Sclerosis Astrocytomas

Project description:Somatic retrotranspositions of various mobile genetic elements take place in tumors, and L1 retroelements physiologically transpose in neural progenitor cells during neurogenesis. We sequenced whole genomes of the neural progenitor cell-derived subependymal giant cell astrocytomas that typically affect patients suffering from the neurodevelopmental disease Tuberous Sclerosis. Here we show an unprecedented increased L1 retrotransposition in these tumors, with tens of thousands new genomic insertions, that preferentially invade genes involved in neural activity, synaptic transmission and cancer. The prevalent insertions are short, nested in preexisting L1 repeats in the same orientation, trimmed in both the 5’ and 3’ ends, representing unorthodox retrotransposition”. Most somatic L1 inserts in the genomically stable astrocytomas are nested in preexisting L1 elements. This preferred nested integration may act as a “lightning rod” mechanism dampening the effects of massive retrotransposition. In contrast, the enhanced transposition found in genomically unstable breast tumors includes regions of high-density clustered insertion, transposminos. These clustered insertions are expected to be more detrimental, as many of them are non-nested and frequently invade genic and exonic sequences. Exaggerated L1 retrotransposition may be a common stochastic damaging pathway in neurological disorders and cancer.

2016-12-31 | GSE56871 | GEO

L1 retrotransposition in neurons is mediated by MeCP2

2010-11-11 | GSE21037 | GEO

L1 retrotransposition in neurons is mediated by MeCP2

Project description:L1 retrotransposons are active elements in the genome, capable of mobilization in neuronal progenitor cells. Previously, we showed that chromatin remodeling during neuronal differentiation allows for a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can impact gene expression and neuronal function. Here we show that L1 neuronal retrotransposition in rodents is increased in the absence of MeCP2, a protein involved in global methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that Rett syndrome patients, with MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition, thereby increasing brain-specific genetic mosaicism. Genetic reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, or iPSCs) by over-expression of specific genes has been accomplished for fibroblasts derived from controls and Rett syndrome patients. Different clones from each were compared to respective original fibroblasts and a human embryonic stem cell line. Gene expression profiles measured using human genome Affymetrix Gene Chip arrays were grouped by hierarchical clustering, and correlation coefficients were computed for all pair-wise comparisons.

2010-11-11 | E-GEOD-21037 | biostudies-arrayexpress

TDP-43 safeguards the embryo genome from L1 retrotransposition

Project description:We report that TAR DNA binding protein 43 (TDP-43), mutations in which constitute a major risk factor for amyotrophic lateral sclerosis (ALS), inhibits L1 retrotransposition in mouse embryonic stem cells (mESCs) and preimplantation embryos. Knockdown of TDP-43 resulted in massive genomic L1 expansion and impaired cell growth in preimplantation embryos and ESCs. Functional analysis demonstrated that TDP-43 interacts with L1 open reading frame 1 protein (L1 ORF1p) to mediate genomic protection, and loss of this interaction led to de-repression of L1 retrotransposition. Our results identify TDP-43 as a guardian of the embryonic genome by protecting it from massive L1 retrotransposition.

2023-01-04 | GSE199197 | GEO

Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation

Project description:Vitamin C (vitC) enhances the activity of 2-oxoglutarate-dependent dioxygenases, including TET enzymes, which catalyse DNA demethylation, and Jumonji-domain histone demethylases. The epigenetic remodelling promoted by vitC improves the efficiency of induced pluripotent stem cell derivation, and is required to attain a ground-state of pluripotency in embryonic stem cells (ESCs) that closely mimics the inner cell mass of the early blastocyst. However, genome-wide DNA and histone demethylation can lead to upregulation of transposable elements (TEs), and it is not known how vitC addition in culture media affects TE expression in pluripotent stem cells. Here, we show that vitC increases the expression of evolutionarily young LINE-1 (L1) elements in mouse ESCs. We find that TET activity is dispensable for these effects, as and that instead L1 upregulation occurs largely as a result of H3K9me3 loss mediated by KDM4A/C histone demethylases. Despite increased L1 levels, we find no evidence of substantially higher retrotransposition rates, suggesting that downstream mechanisms restrict L1 mobility. Notably, treatment of human ESCs with vitC also increases L1 protein levels, which could impact the genetic and epigenetic stability of human pluripotent stem cells.

2023-08-07 | GSE238224 | GEO

The RIG-I like receptor LGP2 inhibits Dicer-dependent processing of long double-stranded RNA and blocks RNA interference in mammalian cells.

Project description:In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG-I like receptor (RLR) family , which signal to induce production of type I interferons (IFN). These key anti-viral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon-stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG-I, MDA5 and the least-studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus-derived double stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We identify Dicer as an LGP2-associated protein and show that LGP2 inhibits Dicer cleavage of dsRNA into siRNAs both in vitro and in vivo. Further, we show that in cells lacking an IFN response, ectopic expression of LGP2 interferes with RNAi-dependent suppression of gene expression. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs.

2018-01-17 | PXD008364 | Pride

Somatic L1 retrotranspositions in normal human cells

Project description:Genomic mutations accumulate in normal cells during lifetime; however, somatic mosaicism generated by mobilization of transposable elements is not well understood. Here, we sequenced 880 normal colonic crypt, 12 colonic crypt from adenomatous polyp, and 19 colorectal cancers from 20 individuals. Most of the colorectal epithelial cells acquired somatic L1 retrotranspositions and the burden is ~10-fold increased in cancer tissues. Among 34 source elements in our cohort, 44% of them are new, often private in an individual, suggesting ongoing emergence of active L1 sources in humans. L1 insertion is more frequent during early embryogenesis period probably due to global hypomethylation. The hot L1s always contain demethylated promoters, suggesting the hypothesis that some L1s which accidentally avoid remethylation remain transcriptionally active and cause L1 retrotransposition events along the cellular lineages.

| EGAS00001006213 | EGA

A non-Dicer RNase III and four other novel factors required for RNAi-mediated transposon suppression in the human pathogenic yeast C. neoformans

Project description:The human pathogenic yeast Cryptococcus neoformans silences transposable elements using endo-siRNAs and an Argonaute, Ago1. Endo-siRNAs production requires the RNA-dependent RNA polymerase, Rdp1, and two partially redundant Dicer enzymes, Dcr1 and Dcr2, but is independent of histone H3 lysine 9 methylation. We describe here an insertional mutagenesis screen for factors required to suppress the mobilization of the C. neoformans HARBINGER family DNA transposon HAR1. Validation experiments uncovered five novel genes (RDE1-5) required for HAR1 suppression and global production of suppressive endo-siRNAs. The RDE genes impact global siRNA levels and transposon mobilization but not global transcript levels, suggesting the endo-siRNAs do not act by impacting target transcript synthesis or turnover. RDE3 encodes a non-Dicer RNase III related to S. cerevisiae Rnt1, RDE4 encodes a predicted terminal nucleotidyltransferase, while RDE5 has no strongly predicted encoded domains. Affinity purification-mass spectrometry studies reveal that Rde3 and Rde5 are physically associated. RDE1 encodes a G-patch protein homologous to the S. cerevisiae Sqs1/Pfa1, a nucleolar protein that directly activates the essential helicase Prp43 during rRNA biogenesis. Rde1 copurifies Rde2, another novel protein obtained in the screen, as well as Ago1, a homolog of Prp43, and numerous predicted nucleolar proteins. We also describe the isolation of conditional alleles of PRP43, which are defective in RNAi. This work reveals unanticipated requirements for a non-Dicer RNase III and presumptive nucleolar factors for endo-siRNA biogenesis and transposon mobilization suppression in C. neoformans.

2020-07-13 | GSE128009 | GEO

Small RNAs in budding yeast

Project description:RNAi, a gene-silencing pathway triggered by double-stranded RNA, is conserved in diverse eukaryotic species but has been lost in the model budding yeast, Saccharomyces cerevisiae. We report that RNAi is present in other budding-yeast species, including Saccharomyces castellii and Candida albicans. These species use noncanonical Dicer proteins to generate siRNAs, which mostly correspond to transposable elements and Y´ subtelomeric repeats. In S. castellii, RNAi mutants are viable but have excess Y´ mRNA levels. In S. cerevisiae, introducing Dicer and Argonaute of S. castellii restores RNAi, and the reconstituted pathway silences endogenous retrotransposons. These results identify a novel class of Dicer proteins, bring the tool of RNAi to the study of budding yeasts, and bring the tools of budding yeast to the study of RNAi.

2009-09-10 | GSE17871 | GEO

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