Mouse germ line mutations due to retrotransposon insertions

Gagnier, Liane; Belancio, Victoria P.; Mager, Dixie L.

doi:10.1186/s13100-019-0157-4

Cited by 88 publications

(97 citation statements)

References 288 publications

(308 reference statements)

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“…It is remarkable that no active DNA transposons have been identified in humans and mice [37] nor in the vast majority of mammals, with the exception of some bat species [38][39][40][41], thus limiting the possibility to investigate in these species the short-term effect of insertions mediated by this group of TEs. D. melanogaster as well as other Drosophila species, are therefore promising model organisms for studying the contribution to regulatory sequences by eukaryotic TEs.…”

Section: Drosophila Tes: a Brief Overviewmentioning

confidence: 99%

“What You Need, Baby, I Got It”: Transposable Elements as Suppliers of Cis-Operating Sequences in Drosophila

Moschetti

Palazzo

Lorusso

et al. 2020

Biology

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Transposable elements (TEs) are constitutive components of both eukaryotic and prokaryotic genomes. The role of TEs in the evolution of genes and genomes has been widely assessed over the past years in a variety of model and non-model organisms. Drosophila is undoubtedly among the most powerful model organisms used for the purpose of studying the role of transposons and their effects on the stability and evolution of genes and genomes. Besides their most intuitive role as insertional mutagens, TEs can modify the transcriptional pattern of host genes by juxtaposing new cis-regulatory sequences. A key element of TE biology is that they carry transcriptional control elements that fine-tune the transcription of their own genes, but that can also perturb the transcriptional activity of neighboring host genes. From this perspective, the transposition-mediated modulation of gene expression is an important issue for the short-term adaptation of physiological functions to the environmental changes, and for long-term evolutionary changes. Here, we review the current literature concerning the regulatory and structural elements operating in cis provided by TEs in Drosophila. Furthermore, we highlight that, besides their influence on both TEs and host genes expression, they can affect the chromatin structure and epigenetic status as well as both the chromosome's structure and stability. It emerges that Drosophila is a good model organism to study the effect of TE-linked regulatory sequences, and it could help future studies on TE-host interactions in any complex eukaryotic genome.

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Section: Drosophila Tes: a Brief Overviewmentioning

confidence: 99%

“What You Need, Baby, I Got It”: Transposable Elements as Suppliers of Cis-Operating Sequences in Drosophila

Moschetti

Palazzo

Lorusso

et al. 2020

Biology

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“…This subclass contains a 1.9 kb deletion affecting gag and pol, creating a gag-pol fusion gene and protein which facilitates its own retrotransposition (Saito et al 2008). Notably, nearly all recent activity of the IAP family, as judged by germ line mutations due to IAP insertions, involve 1Δ1 elements (Gagnier et al 2019). The degree of similarity between the identities of the current Cdk5rap1-IAP and Stab2-IAP suggests that a burst of IAP insertions took place in parental genome and the two IAPs were fixed differentially during the establishment of individual inbred strains in early 1900s, rather than that the transpositions occurred and fixed independently in C57BL/6J line and in DBA line (Beck et al 2000).…”

Section: Insertion Of An Iap Element Within the Promoter Region Of Thmentioning

confidence: 99%

“…Although the IAP is in an opposite transcriptional orientation relative to that of Stab2 DBA , an antisense promoter within the 5′LTR can initiate reverse-oriented transcription and cause disturbance of the normal transcription of nearby genes (Chuong et al 2017;Gagnier et al 2019;Thompson et al 2016). To confirm that the Stab2 DBA transcription is driven by the 5′LTR in vivo, we performed reverse transcription PCR using RNA from tissues using a forward primer corresponding to a sequence within the 5′LTR and a reverse primer corresponding to a sequence in the Stab2 exon 3 (Fig.…”

Section: ′Ltr Of the Stab2-iap Drives The Stab2 Dba Gene Expression mentioning

confidence: 99%

Ectopic expression of the Stabilin2 gene triggered by an intracisternal A particle (IAP) element in DBA/2J strain of mice

et al. 2020

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Stabilin2 (Stab2) encodes a large transmembrane protein which is predominantly expressed in the liver sinusoidal endothelial cells (LSECs) and functions as a scavenger receptor for various macromolecules including hyaluronans (HA). In DBA/2J mice, plasma HA concentration is ten times higher than in 129S6 or C57BL/6J mice, and this phenotype is genetically linked to the Stab2 locus. Stab2 mRNA in the LSECs was significantly lower in DBA/2J than in 129S6, leading to reduced STAB2 proteins in the DBA/2J LSECs. We found a retrovirus-derived transposable element, intracisternal A particle (IAP), in the promoter region of Stab2 DBA which likely interferes with normal expression in the LSECs. In contrast, in other tissues of DBA/2J mice, the IAP drives high ectopic Stab2 DBA transcription starting within the 5′ long terminal repeat of IAP in a reverse orientation and continuing through the downstream Stab2 DBA . Ectopic transcription requires the Stab2-IAP element but is dominantly suppressed by the presence of loci on 59.7-73.0 Mb of chromosome (Chr) 13 from C57BL/6J, while the same region in 129S6 requires additional loci for complete suppression. Chr13:59.9-73 Mb contains a large number of genes encoding Krüppel-associated box-domain zinc-finger proteins that target transposable elements-derived sequences and repress their expression. Despite the high amount of ectopic Stab2 DBA transcript in tissues other than liver, STAB2 protein was undetectable and unlikely to contribute to the plasma HA levels of DBA/2J mice. Nevertheless, the IAP insertion and its effects on the transcription of the downstream Stab2 DBA exemplify that stochastic evolutional events could significantly influence susceptibility to complex but common diseases.

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“…However, ERVs potentially compromise genomic integrity by disrupting gene structure and expression, and by triggering chromosome rearrangements 7 . In laboratory mice, roughly 12% of all pathological mutations result from ERV integration events, half of which emanate from a single family of the ERVK class, the Intracisternal A particles (IAP), that comprise ∼2800 full-length copies 8 . In contrast, human-specific ERVs are mostly transposition-defective 8 .…”

Section: Main Textmentioning

confidence: 99%

m⁶A RNA methylation regulates the fate of endogenous retroviruses

Chelmicki

Roger

Teissandier

et al. 2020

Preprint

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27 28 29 Endogenous retroviruses (ERVs) are abundant and heterogenous groups of integrated 30 retroviral sequences that impact genome regulation and cell physiology throughout 31 their RNA-centered life cycle 1 . Failure to repress ERVs is associated with cancer, 32 infertility, senescence and neurodegenerative diseases 2-4 . Here, using an unbiased 33 genome-scale CRISPR knockout screen in mouse embryonic stem cells, we identify 34 m 6 A RNA methylation as a novel means of ERV restriction. Methylation of ERV mRNAs 35 is catalyzed by the complex of methyltransferase-like METTL3/METTL14 5 proteins 36 whose depletion, along with their accessory subunits, WTAP and ZC3H13, led to 37 increased mRNA abundance of Intracisternal A-particles (IAPs) and related ERVK 38 elements specifically, by targeting their 5'UTR region. Using controlled auxin-39 dependent degradation of the METTL3/METTL14 enzymatic complex, we showed that 40 IAP mRNA and protein abundance is dynamically and inversely correlated with m 6 A 41 catalysis. By monitoring mRNA degradation rates upon METTL3/14 double degron, we 42 further proved that m 6 A methylation destabilizes IAP transcripts. Finally, similarly to 43 m 6 A writers, triple knockout of the m 6 A readers YTHDF1, DF2 and DF3 6 increased IAP 44 mRNA abundance. This study sheds light onto a novel function of RNA methylation in 45 protecting cellular integrity by clearing reactive ERV-derived RNA species, which may 46 be especially important when transcriptional silencing is less stringent.repressors, by transducing cells with single guide (sg)RNAs against the KRAB-associated 80 protein 1 (KAP1) 11 (Extended Data Fig. 1d,e, Supplementary Fig. 1, Supplementary Table 2, 81 Supplementary Table 3). 4For the screen, we transduced IAPEz-reporter cells with a lentiviral genome-wide 83 sgRNA library at multiplicity of infection (MOI)= 0.2-0.3 12 (Fig. 1b). Frequencies of sgRNAs 84 upon blasticidin selection (5, 7 and 9 days) versus non-selected conditions were assessed 85 via deep sequencing and candidate genes were identified using Model-based Analysis of 86 Genome-wide CRISPR/Cas9 Knockout (MAGeCK) 13 . Efficiency of selection was evidenced 87 by drop-out of control intergenic sgRNAs and genes were ranked based on sgRNA P-values 88 ( Fig. 1c, Supplementary Table 4, Supplementary Table 5). Although genome-wide screens of 89 this magnitude typically suffer from low-statistical confidence, we identified several-but not 90 all-genes previously associated with ERV repression (Resf1, Trp53, Daxx, Atrx, Uhrf1, 91 Cbx1, Dnmt1) 14-17 among the top 100 hits. Obtaining an incomplete list of known regulators 92 is a common outcome of genome-wide screens which can be due to multiple factors 93 including time-dependent dropout of essential genes with strong effects on cell viability (such 94 as Kap1) 18 , heterogeneity in sgRNA efficiencies or limited representation of sgRNAs. 95Nonetheless, we were able to identify several novel candidates for IAP control 96( Supplementary Table 4), offering a foundation for futu...

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Mouse germ line mutations due to retrotransposon insertions

Cited by 88 publications

References 288 publications

“What You Need, Baby, I Got It”: Transposable Elements as Suppliers of Cis-Operating Sequences in Drosophila

“What You Need, Baby, I Got It”: Transposable Elements as Suppliers of Cis-Operating Sequences in Drosophila

Ectopic expression of the Stabilin2 gene triggered by an intracisternal A particle (IAP) element in DBA/2J strain of mice

m⁶A RNA methylation regulates the fate of endogenous retroviruses

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Mouse germ line mutations due to retrotransposon insertions

Cited by 88 publications

References 288 publications

“What You Need, Baby, I Got It”: Transposable Elements as Suppliers of Cis-Operating Sequences in Drosophila

“What You Need, Baby, I Got It”: Transposable Elements as Suppliers of Cis-Operating Sequences in Drosophila

Ectopic expression of the Stabilin2 gene triggered by an intracisternal A particle (IAP) element in DBA/2J strain of mice

m6A RNA methylation regulates the fate of endogenous retroviruses

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m⁶A RNA methylation regulates the fate of endogenous retroviruses