Human L1 Retrotransposon Encodes a Conserved Endonuclease Required for Retrotransposition

Feng, Qinghua; Moran, John V.; Kazazian, Haig H.; Boeke, Jef D.

doi:10.1016/s0092-8674(00)81997-2

Cited by 1,041 publications

(1,149 citation statements)

References 56 publications

(26 reference statements)

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“…Indeed, the factor IX gene has been shown to be targeted by one disease-causing LINE-1 insertion and two independent Alu insertions (Ostertag and Kazazian, 2001) suggesting that Alu and LINE-1 elements can share an insertion hotspot. The notion that Alu and LINE-1 elements have different insertion biases is also inconsistent with the finding that evolutionarily recent insertions of active Alu and LINE-1 subfamilies do not follow the non-random genomic distribution of the older elements (Feng et al, 1996;Ovchinnikov et al, 2001;Gilbert et al, 2002;Symer et al, 2002;Szak et al, 2002;Gilbert et al, 2005). Indeed, we show that all older (>2.4 myr) Alu subfamilies examined are significantly more abundant around housekeeping genes than tissue-specific genes while this trend is weaker or not evident among the youngest subfamilies.…”

Section: The Possibility That Non-random Insertion Patterns Contributmentioning

confidence: 85%

“…Alu elements might preferentially recognize the chromatin near housekeeping genes while LINE-1 elements and other long transposons avoid such chromatin. However, the notion of strikingly distinct insertion biases seems contrary to the finding that the LINE-1 transposition machinery mobilizes both LINE-1 and Alu elements (Jurka, 1997;Dewannieux et al, 2003) which consequently insert at the same consensus TT/AAAA sequence (Feng et al, 1996;Jurka, 1997;Cost and Boeke, 1998). Indeed, the factor IX gene has been shown to be targeted by one disease-causing LINE-1 insertion and two independent Alu insertions (Ostertag and Kazazian, 2001) suggesting that Alu and LINE-1 elements can share an insertion hotspot.…”

Section: The Possibility That Non-random Insertion Patterns Contributmentioning

confidence: 86%

“…Alu transposons differ from other SINEs in that they are not derived from tRNA genes, but rather from the 7SL RNA gene (Ullu and Tschudi, 1984;Quentin, 1994;Smit, 1996;Okada and Hamada, 1997;Terai et al, 1998;Lander et al, 2001) which encodes the RNA component of the signal recognition particle that mediates the translocation of nascent secretory and membrane proteins (Wild et al, 2004). Aside from favoring TT|AAAA target sequences (Feng et al, 1996;Jurka, 1997;Cost and Boeke, 1998), human Alu and LINE-1 elements have been reported to insert at random positions in the genome (Smit, 1999;Boissinot et al, 2001;Lander et al, 2001;Ovchinnikov et al, 2001;Gilbert et al, 2002;Myers et al, 2002;Symer et al, 2002;Szak et al, 2002;Jurka et al, 2004;Gilbert et al, 2005). However, there is some evidence for insertional hot spots (Cost and Boeke, 1998;Myers et al, 2002;Graham and Boissinot, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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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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Section: The Possibility That Non-random Insertion Patterns Contributmentioning

confidence: 85%

Section: The Possibility That Non-random Insertion Patterns Contributmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Repetitive sequence environment distinguishes housekeeping genes

Eller¹,

Regelson²,

Merriman³

et al. 2007

Gene

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“…Human L1 contains two open reading frames, ORF1 and ORF2, which encode a protein with RNA-binding and nucleotide acid-chaperone activity (ORF1) 11 and a protein with endonuclease and reverse-transcriptase activities (ORF2) [12][13][14][15] , respectively. L1 mobilizes replicatively from one location in the genome to another by a 'copy-and-paste' mechanism, and it has been proposed to be a remnant of an ancient retrovirus 12,16 .…”

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confidence: 99%

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Hamdorf

Idica

Zisoulis

et al. 2015

Nat Struct Mol Biol

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VOLUME 22 NUMBER 10 OCTOBER 2015 nature structural & molecular biology a r t i c l e s microRNAs (miRs) are a class of small (~22-nt) genomically encoded molecules that inhibit translational initiation and stimulate decay of mRNA targets 1,2 . miRs are transcribed by RNA polymerase II and processed by the RNase III enzymes-Dicer and Drosha with its binding partner, DGCR8-to produce short double-stranded RNAs in the nucleus. One strand associates with the Argonaute (Ago) protein, thus forming the miR-mediated silencing complex (miRISC). miRs guide the pairing of miRISC, with imperfect complementarity, to sequences in target mRNAs, thus resulting in their subsequent destabilization and translational repression of the target 3 . The 'seed sequence' , at nucleotides 2-8, is a key determinant for miRISC-target recognition 4,5 . Recent data have shown that 35-40% of miR-binding sites are found in 3′ untranslated regions (UTRs), 40-50% in coding regions and <5% in 5′-UTR regions of mRNAs 6,7 . More than 60% of the human transcriptome has been predicted to be under miR regulation, thus making this post-transcriptional control pathway as important as protein pathways in the regulation of cell functions 2 . It is clear that miRs have essential roles in regulating diverse functions in normal and diseased cells 8,9 .L1 belongs to the most abundant class of autonomous transposable elements 10 . Human L1 contains two open reading frames, ORF1 and ORF2, which encode a protein with RNA-binding and nucleotide acid-chaperone activity (ORF1) 11 and a protein with endonuclease and reverse-transcriptase activities (ORF2) 12-15 , respectively. L1 mobilizes replicatively from one location in the genome to another by a 'copy-and-paste' mechanism, and it has been proposed to be a remnant of an ancient retrovirus 12,16 . Active and inactive L1s have been implicated in the evolution of mammalian genomes and are linked to cell-based diseases, including cancer [17][18][19] . In addition, somatic L1 insertions are biased toward regions of cancer-specific DNA hypomethylation, thus suggesting that L1 insertions may provide a selective advantage during tumorigenesis 20 . Mechanisms that operate at different levels in gene-expression hierarchies have been selected to control transposition-mediated mutagenesis and mitigate the potential negative effects of newly inserted elements. In germ cells, a specific small-RNA subtype (piwi-interacting RNAs (piRNAs)) efficiently counteracts L1 activity, but these RNAs are not expressed in nongerm cells 21,22 . Somatic cells attenuate element mobilization by DNA methylation of the L1 promoter 23 . Other methods of regulation are mediated by APOBEC proteins 24,25 , microprocessor interactions 26 and Ago-mediated RNA interference in mouse embryonic stem cells 27 . L1-promoter silencing is greatly attenuated, and L1 transcription is reactivated in hypomethylated cells, such as cancer cells and tumor-initiating cells, and is also reactivated during reprogramming [28][29][30] . Because miRs act as regulators of g...

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“…Full‐length L1s are ~6 kb long, with a promoter, 5' and 3' untranslated regions, and two open reading frames (ORFs) (Scott et al., 1987). ORF1 encodes an RNA‐binding protein (Martin, 2010) and ORF2 encodes an endonuclease and reverse transcriptase (Feng, Moran, Kazazian, & Boeke, 1996; Mathias, Scott, Kazazian, Boeke, & Gabriel, 1991) that enable L1s to replicate by a “copy‐and‐paste” mechanism to move and accumulate within the genome. Most L1s have lost “genomic mobility” due to truncations or mutations; however, about 100 full‐length L1s in an average human genome, mostly L1Hs T a subfamily members, remain “competent” to replicate and insert at a new locus (Richardson et al., 2015).…”

Section: Introductionmentioning

confidence: 99%

Reading LINEs within the cocaine addicted brain

Doyle

Doucet-O’Hare²,

Hammond

et al. 2017

Brain and Behavior

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IntroductionLong interspersed element (LINE)‐1 (L1) is a type of retrotransposon capable of mobilizing into new genomic locations. Often studied in Mendelian diseases or cancer, L1s may also cause somatic mutation in the developing central nervous system. Recent reports showed L1 transcription was activated in brains of cocaine‐treated mice, and L1 retrotransposition was increased in cocaine‐treated neuronal cell cultures. We hypothesized that the predisposition to cocaine addiction may result from inherited L1s or somatic L1 mobilization in the brain.MethodsPostmortem medial prefrontal cortex (mPFC) tissue from 30 CA and 30 control individuals was studied. An Alexafluor488‐labeled NeuN antibody and fluorescence activated nuclei sorting were used to separate neuronal from non‐neuronal cell nuclei. L1s and their 3' flanking sequences were amplified from neuronal and non‐neuronal genomic DNA (gDNA) using L1‐seq. L1 DNA libraries from the neuronal gDNA were sequenced on an Illumina HiSeq2000. Sequences aligned to the hg19 human genome build were analyzed for L1 insertions using custom “L1‐seq” bioinformatics programs.ResultsPreviously uncataloged L1 insertions, some validated by PCR, were detected in neurons from both CA and control brain samples. Steady‐state L1 mRNA levels in CA and control mPFC were also assessed. Gene ontology and pathway analyses were used to assess relationships between genes putatively disrupted by novel L1s in CA and control individuals. L1 insertions in CA samples were enriched in gene ontologies and pathways previously associated with CA.ConclusionsWe conclude that neurons in the mPFC harbor L1 insertions that have the potential to influence predisposition to CA.

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Human L1 Retrotransposon Encodes a Conserved Endonuclease Required for Retrotransposition

Cited by 1,041 publications

References 56 publications

Repetitive sequence environment distinguishes housekeeping genes

Repetitive sequence environment distinguishes housekeeping genes

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

Reading LINEs within the cocaine addicted brain

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