Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes

Han, Jeffrey S.; Szak, Suzanne; Boeke, Jef D.

doi:10.1038/nature02536

Cited by 464 publications

(449 citation statements)

References 48 publications

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“…They can generate structural variation through insertion-mediated deletion, in which the insertion of an L1 element can result in the deletion of the adjacent genomic sequence (Symer et al 2002;Gilbert et al 2002Gilbert et al , 2005 and via nonallelic homologous recombination between L1s that can create insertions, deletions, and inversions (Han et al 2008;Cordaux and Batzer 2009). Active L1s have been shown to be a major source of variation within the human population (Beck et al 2010;Huang et al 2010;Iskow et al 2010) and can modulate gene expression, for example, by alternative splicing (Belancio et al 2006), disrupting transcription (Han et al 2004), and generating alternative promoters (Speek 2001).…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

et al. 2018

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Approximately half the mammalian genome is composed of repetitive sequences, and accumulating evidence suggests that some may have an impact on genome function. Here, we characterized a large array class of repeats of long-interspersed elements (LINE-1). Although widely distributed in mammals, locations of such arrays are species specific. Using targeted deletion, we asked whether a 170-kb LINE-1 array located at a mouse imprinted domain might function as a modulator of local transcriptional control. The LINE-1 array is lamina associated in differentiated ES cells consistent with its AT-richness, and although imprinting occurs both proximally and distally to the array, active LINE-1 transcripts within the tract are biallelically expressed. Upon deletion of the array, no perturbation of imprinting was observed, and abnormal phenotypes were not detected in maternal or paternal heterozygous or homozygous mutant mice. The array does not shield nonimprinted genes in the vicinity from local imprinting control. Reduced neural expression of protein-coding genes observed upon paternal transmission of the deletion is likely due to the removal of a brain-specific enhancer embedded within the LINE array. Our findings suggest that presence of a 170-kb LINE-1 array reflects the tolerance of the site for repeat insertion rather than an important genomic function in normal development.

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Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

et al. 2018

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“…Although transposable elements may contribute to genome evolution (Kazazian 2004), they can disrupt genes at their insertion sites (Han et al 2004). To secure the genome of future generations from de novo insertion mutations, transposable elements should be tightly controlled in germ cells.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

Targeted gene silencing in mouse germ cells by insertion of a homologous DNA into a piRNA generating locus

et al. 2012

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In germ cells, early embryos, and stem cells of animals, PIWI-interacting RNAs (piRNAs) have an important role in silencing retrotransposons, which are vicious genomic parasites, through transcriptional and post-transcriptional mechanisms. To examine whether the piRNA pathway can be used to silence genes of interest in germ cells, we have generated knock-in mice in which a foreign DNA fragment was inserted into a region generating pachytene piRNAs. The knock-in sequence was transcribed, and the resulting RNA was processed to yield piRNAs in postnatal testes. When reporter genes possessing a sequence complementary to portions of the knock-in sequence were introduced, they were greatly repressed after the time of pachytene piRNA generation. This repression mainly occurred at the post-transcriptional level, as degradation of the reporter RNAs was accelerated. Our results show that the piRNA pathway can be used as a tool for sequence-specific gene silencing in germ cells and support the idea that the piRNA generating regions serve as traps for retrotransposons, enabling the host cell to generate piRNAs against active retrotransposons.

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“…For each gene, we initially defined a region of analysis extending from 100-kb upstream of the transcription start position (txStart) to 100-kb downstream of the transcription end position (txEnd). We excluded the transcribed gene regions from our analysis to avoid effects that can be attributed to displacement by the coding sequence or splicing elements, or to the interference of transcriptional elongation by repetitive sequences in introns (Han et al, 2004). Gaps in the DNA sequence were also omitted.…”

Section: Sequence Characteristicsmentioning

confidence: 99%

“…For each gene, we initially considered a region extending 100-kb upstream from the transcription start and 100-kb downstream from the transcription end, but excluding the transcribed gene region. We excluded the transcribed regions from our analysis to avoid effects attributable to displacement by the coding sequence or splicing elements, or to the interference of transcriptional elongation by repetitive sequences in introns (Han et al, 2004). For the 200-kb region flanking each gene, we identified the types and positions of repeats from the RepeatMasker output provided by the UCSC genome browser (http://genome.ucsc.edu) (Supplementary Table 1 online).…”

Section: Differences In Flanking Sequence Composition Between Housekementioning

confidence: 99%

“…Housekeeping genes also typically have small introns (Eisenberg and Levanon, 2003) that lack repetitive sequences (Han et al, 2004). Housekeeping genes have been found to cluster together on the genome to some degree (Lercher et al, 2002), and to preferentially localize to GC-rich fractions of genomic DNA known as isochores on cesium sulfate gradients (Lercher et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

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Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element 1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, were used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.

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Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes

Cited by 464 publications

References 48 publications

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

Targeted deletion of a 170-kb cluster of LINE-1 repeats and implications for regional control

Targeted gene silencing in mouse germ cells by insertion of a homologous DNA into a piRNA generating locus

Repetitive sequence environment distinguishes housekeeping genes

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