Hot L1s account for the bulk of retrotransposition in the human population

Brouha, Brook; Schustak, Joshua; Badge, Richard M.; Lutz, Sheila; Farley, Alexander H.; Moran, John V.; Kazazian, Haig H.

doi:10.1073/pnas.0831042100

Cited by 955 publications

(1,137 citation statements)

References 46 publications

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“…We have now investigated the response of these cells after silencing, or efficiently downregulating L1 activity by stable RNAi. To this end, A-375 cells were infected with a retroviral vector containing the construct, expressing a 19 bp double-stranded RNA oligonucleotide directed against the ORF1-coding region of functional human L1 elements pS-L1i (Figure 1a) (Brouha et al, 2003). The effectiveness of interference against L1 expression compared to control cells infected with empty vector (pS-neo) was assessed by immunofluorescence (IF), RT-PCR and immunoblotting analyses.…”

Section: Resultsmentioning

confidence: 99%

“…To generate the L1 interfering construct pS-L1i, the 19-bp L1-targeted siRNA double-stranded oligonucleotide GA-GAACGCCACAAAGATAC was designed to target specifically the sequence 1492-1511 of active L1 elements as described (see supporting information Figure 6b in Brouha et al, 2003). The 19-bp L1-specific oligonucleotide and a 17-bp scrambled oligonucleotide (GATCCCCTTTTTGGAAA) as control were inserted into the pS-neo/EGFP vector (Oligoengine, Seattle, WA, USA, PRT-0006), previously digested with BglII and HindIII restriction enzymes, generating pS-L1i and pS-scrambled constructs, respectively.…”

Section: Assembly Of the Retroviral Delivery Vector And Cell Infectionmentioning

confidence: 99%

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Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

et al. 2007

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Transformed cells express high levels of non-telomeric reverse-transcriptase (RT) activity of retrotransposon and endogenous retrovirus origin. We previously reported that RT inhibition, either pharmacological or through transient silencing of RT-encoding LINE-1 (L1) elements by RNA interference (RNAi), reduced proliferation, induced differentiation and reprogrammed gene expression in human tumorigenic cell lines. Moreover, the antiretroviral drug efavirenz antagonized tumor progression in animal models in vivo. To get insight into the role of retroelements in tumorigenesis, we have now produced two cell lines derived from A-375 melanoma, in which the expression of either L1 retrotransposon, or HERV-K endogenous retrovirus, was stably suppressed by RNAi. Compared to the parental A-375 cell line, cells with stably interfered L1 expression show a lower proliferation rate, a differentiated morphology and lower tumorigenicity when inoculated in nude mice. L1 silencing modulates expression of several genes and, unexpectedly, also downregulates HERV-K expression. In HERV-K interfered cells, instead, L1 expression was unaffected, and cell proliferation and differentiation remained unchanged compared to parental A-375 cells. In vivo, however, their tumorigenic potential was found to be reduced after inoculation in nude mice. These results suggest that L1 and HERV-K play specific and distinct roles in cell transformation and tumor progression.

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Section: Resultsmentioning

confidence: 99%

Section: Assembly Of the Retroviral Delivery Vector And Cell Infectionmentioning

confidence: 99%

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

et al. 2007

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“…LINE-1 (L1) is the youngest of the four families and the major LINE family in eutherian and marsupial mammals. There are thought to be approximately 3000 active L1s in the mouse genome (Goodier et al 2001) and around 100 in the human (Brouha et al 2003). In the mouse there are three families of active L1s: L1md_A, L1Md_Gf, and L1Md_Tf (DeBerardinis et al 1998;Goodier et al 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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“…To address this question, RNAi experiments were designed to target specifically LINE-1 element families that are most abundantly expressed in human cells (Brouha et al, 2003, and . Neither LINE-1 nor lamin RNAi influenced GAPDH expression.…”

Section: Rna Interference (Rnai) Against Rt-encoding Line-1 Elementsmentioning

confidence: 99%

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth

et al. 2005

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Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy.

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Hot L1s account for the bulk of retrotransposition in the human population

Cited by 955 publications

References 46 publications

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

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

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth

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