Transcription of transposable elements interspersed in the genome
is controlled by complex interactions between their regulatory
elements and host factors. However, the same regulatory elements
may be occasionally used for the transcription of host genes. One
such example is the human L1 retrotransposon, which contains an
antisense promoter (ASP) driving transcription into adjacent genes
yielding chimeric transcripts. We have characterized 49 chimeric
mRNAs corresponding to sense and antisense strands of human genes.
Here we show that L1 ASP is capable of functioning as an
alternative promoter, giving rise to a chimeric transcript whose
coding region is identical to the ORF of mRNA of the following
genes: KIAA1797, CLCN5, and SLCO1A2.
Furthermore, in these cases the activity of L1 ASP is
tissue-specific and may expand the expression pattern of the
respective gene. The activity of L1 ASP is tissue-specific also in
cases where L1 ASP produces antisense RNAs complementary to
COL11A1 and BOLL mRNAs. Simultaneous assessment
of the activity of L1 ASPs in multiple loci revealed the presence
of L1 ASP-derived transcripts in all human tissues examined. We
also demonstrate that L1 ASP can act as a promoter in vivo and
predict that it has a heterogeneous transcription initiation site.
Our data suggest that L1 ASP-driven transcription may increase the
transcriptional flexibility of several human genes.

Kert Mätlik

Kaja Redik

Mart Speek

L1 Antisense Promoter Drives Tissue-Specific Transcription
of Human Genes

LINE-1 (L1) retrotransposons constitute the most successful family of retroelements in mammals and account for as much as 20&#37; of mammalian DNA. L1 elements can be found in all genomic regions but they are far more abundant in AT-rich, gene-poor, and low-recombining regions of the genome. In addition, the sex chromosomes and some genes seem disproportionately enriched in L1 elements. Insertion bias and selective processes can both account for this biased distribution of L1 elements. L1 elements do not appear to insert randomly in the genome and this insertion bias can at least partially explain the genomic distribution of L1. The contrasted distribution of L1 and Alu elements suggests that postinsertional processes play a major role in shaping L1 distribution. The most likely mechanism is the loss of recently integrated L1 elements that are deleterious (negative selection) either because of disruption of gene function or their ability to mediate ectopic recombination. By comparison, the retention of L1 elements because of some positive effect is limited to a small fraction of the genome. Understanding the respective importance of insertion bias and selection will require a better knowledge of insertion mechanisms and the dynamics of L1 inserts in populations.

Todd  Graham

Stephane  Boissinot

The Genomic Distribution of L1 Elements: The Role of Insertion Bias and Natural Selection

Nina Luning Prak

Abdelali  Haoudi

LINE-1 Retrotransposition: Impact on Genome  Stabilityand Diversity and Human Disease

The hypothesis that RNA interference constrains L1 mobility seems
inherently reasonable: L1 mobility can be dangerous and L1 RNA,
the presumed target of RNAi, serves as a critical
retrotransposition intermediate. Despite its plausibility, proof
for this hypothesis has been difficult to obtain. Studies
attempting to link the L1 retrotransposition frequency to
alterations in RNAi activity have been hampered by the long times
required to measure retrotransposition frequency, the pleiotropic
and toxic effects of altering RNAi over similar time periods, and
the possibility that other cellular machinery may contribute to
the regulation of L1s. Another problem is that the commonly used
L1 reporter cassette may serve as a substrate for RNAi. Here we
review the L1-RNAi hypothesis and describe a genetic assay with a
modified reporter cassette that detects approximately 4 times more
L1 insertions than the conventional retrotransposition assay.

Shane R. Horman

Petr Svoboda

Eline T. Luning Prak

The Potential Regulation of L1 Mobility by RNA Interference

There is longstanding evidence that X-chromosome inactivation(XCI) travels less successfully in autosomal than inX-chromosomal chromatin. The interspersed repeatelements LINE1s (L1s) have been suggested as candidates for&#8220;boosters&#8221; which promote the spread of XCI in the X-chromosome.The present paper reviews the current evidence concerning thepossible role of L1s in XCI. Recent evidence, accruing from thehuman genome sequencing project and other sources, confirms thatmammalian X-chromosomes are indeed rich in L1s, except in regionswhere there are many genes escaping XCI. The density of L1s is thehighest in the evolutionarily oldest regions. Recent work on X;autosome translocations in human and mouse suggested failure ofstabilization of XCI in autosomal material, so that genes arereactivated, but resistance of autosomal genes to the originalsilencing is not excluded. The accumulation of L1s on theX-chromosome may have resulted from reduced recombination or latereplication. Whether L1s are part of the mechanism of XCI or aresult of it remains enigmatic.

Mary F. Lyon

Do LINEs Have a Role in X-Chromosome Inactivation?

Barbara McClintock was the first to suggest that transposons are a
source of genome instability and that genotoxic stress assisted in
their mobilization. The generation of double-stranded DNA breaks
(DSBs) is a severe form of genotoxic stress that threatens the
integrity of the genome, activates cell cycle checkpoints, and, in
some cases, causes cell death. Applying McClintock's stress
hypothesis to humans, are L1 retrotransposons, the most active
autonomous mobile elements in the modern day human genome,
mobilized by DSBs? Here, evidence that transposable elements,
particularly retrotransposons, are mobilized by genotoxic stress
is reviewed. In the setting of DSB formation, L1 mobility may be
affected by changes in the substrate for L1 integration, the DNA
repair machinery, or the L1 element itself. The review concludes
with a discussion of the potential consequences of L1 mobilization
in the setting of genotoxic stress.

Evan A. Farkash

DNA Damage and L1 Retrotransposition

LINE-1 (L1) elements are the most abundant autonomous non-LTR retrotransposons in the human genome. Having recently performed a meta-analysis of L1 endonuclease-mediated retrotranspositional
events causing human genetic disease, we have extended this study by focusing on two key issues, namely, mutation detection bias and the multiplicity of mechanisms of target gene disruption. Our analysis
suggests that whereas an ascertainment bias may have generally militated against the detection of autosomal L1-mediated insertions, autosomal L1 direct insertions could have been disproportionately overlooked owing to their unusually large size. Our analysis has also indicated that the mechanisms underlying the functional disruption of target genes by L1-mediated retrotranspositional events are likely to be dependent on several different factors such as the type of insertion (L1 direct, L1 trans-driven Alu, or SVA), the precise locations of the inserted sequences within the target gene regions, the length of the inserted sequences, and possibly also their orientation.

Jian-Min Chen

Claude F&#xe9;rec

David N. Cooper

LINE-1 Endonuclease-Dependent Retrotranspositional Events Causing Human Genetic Disease: Mutation Detection Bias and Multiple Mechanisms of Target Gene Disruption

Chronic feeding of methyl-donor (methionine, choline, folic acid,
and vitamin B12) deficient diet induces hepatocellular carcinoma
formation in rats. Previous studies have shown that promoter CpG
islands in various cancer-related genes are aberrantly methylated
in this model. Moreover, the global genome in
methyl-donor-deficient diet fed rats contains a lesser amount of
5-methylcytosine than control livers. It is speculated that more
than 90% of all 5-methylcytosines lie within the CpG islands of
the transposons, including the long/short interspersed nucleotide
elements (LINE and SINE). It is considered that the
5-methylcytosines in LINE-1 limit the ability of retrotransposons
to be activated and transcribed; therefore, the extent of
hypomethylation of LINE-1 could be a surrogate marker for aberrant
methylation in other tumor-related genes as well as genome
instability. Additionally, LINE-1 methylation status has been
shown to be a good indicator of genome-wide methylation. In this
study, we determined cytosine methylation status in the LINE-1
repetitive sequences of rats fed a choline-deficient (CD) diet for
various durations and compared these with rats fed a
choline-sufficient (CS) diet. The methylation status of LINE-1 was
assessed by the combined bisulfite restriction analysis (COBRA)
method, where the amount of bisulfite-modified and RsaI-cleaved
DNA was quantified using gel electrophoresis. Progressive
hypomethylation was observed in LINE-1 of CD livers as a function
of feeding time; that is, the amount of cytosine in total cytosine
(methylated and unmethylated) increased from 11.1% (1 week) to
19.3% (56 weeks), whereas in the control CS livers, it increased
from 9.2% to 12.9%. Hypomethylation in tumor tissues was
slightly higher (6%) than the nontumorous surrounding tissue. The
present result also indicates that age is a factor influencing the
extent of cytosine methylation.

Kiyoshi Asada

Yashige Kotake

Rumiko Asada

Deborah Saunders

Robert H. Broyles

Rheal A. Towner

Hiroshi Fukui

Robert A. Floyd

LINE-1 Hypomethylation in a Choline-Deficiency-Induced  Liver Cancer in Rats: Dependence on Feeding Period

LINE-1 or L1 is an autonomous non-LTR retrotransposon in mammals.
Retrotransposition requires the function of the two
L1-encoded polypeptides, ORF1p and ORF2p. Early recognition of
regions of homology between the predicted amino acid sequence of
ORF2 and known endonuclease and reverse transcriptase enzymes led
to testable hypotheses regarding the function of ORF2p in
retrotransposition. As predicted, ORF2p has been demonstrated to
have both endonuclease and reverse transcriptase activities. In
contrast, no homologs of known function have contributed to our
understanding of the function of ORF1p during retrotransposition.
Nevertheless, significant advances have been made such that we now
know that ORF1p is a high-affinity RNA-binding protein that forms
a ribonucleoprotein particle together with L1 RNA. Furthermore,
ORF1p is a nucleic acid chaperone and this nucleic acid chaperone
activity is required for L1 retrotransposition.

Sandra L. Martin

The ORF1 Protein Encoded by LINE-1: Structure and Function During L1 Retrotransposition

Retrotransposons like L1 are silenced in somatic cells by avariety of mechanisms acting at different levels. Protectivemechanisms include DNA methylation and packaging into inactivechromatin to suppress transcription and prevent recombination,potentially supported by cytidine deaminase editing of RNA.Furthermore, DNA strand breaks arising during attemptedretrotranspositions ought to activate cellular checkpoints, and L1activation outside immunoprivileged sites may elicit immuneresponses. A number of observations indicate that L1 sequencesnevertheless become reactivated in human cancer. Prominently,methylation of L1 sequences is diminished in many cancer types andfull-length L1 RNAs become detectable, although strong expressionis restricted to germ cell cancers. L1 elements have been found tobe enriched at sites of illegitimate recombination in manycancers. In theory, lack of L1 repression in cancer might causetranscriptional deregulation, insertional mutations, DNA breaks,and an increased frequency of recombinations, contributing togenome disorganization, expression changes, and chromosomalinstability. There is however little evidence that such effectsoccur at a gross scale in human cancers. Rather, as a rule, L1repression is only partly alleviated. Unfortunately, manytechniques commonly used to investigate genetic and epigeneticalterations in cancer cells are not well suited to detect subtleeffects elicited by partial reactivation of retroelements like L1which are present as abundant, but heterogeneous copies.Therefore, effects of L1 sequences exerted on the local chromatinstructure, on the transcriptional regulation of individual genes,and on chromosome fragility need to be more closely investigatedin normal and cancer cells.

Wolfgang A. Schulz

L1 Retrotransposons in Human Cancers

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BioMed Research International

LINE-1 Retrotransposition: Impact on Genome Stability and Diversity and Human Disease

LINE-1 Retrotransposition: Impact on Genome Stability and Diversity and Human Disease

Articles

L1 Antisense Promoter Drives Tissue-Specific Transcription of Human Genes

The Genomic Distribution of L1 Elements: The Role of Insertion Bias and Natural Selection

LINE-1 Retrotransposition: Impact on Genome Stability and Diversity and Human Disease

The Potential Regulation of L1 Mobility by RNA Interference

Do LINEs Have a Role in X-Chromosome Inactivation?

DNA Damage and L1 Retrotransposition

LINE-1 Endonuclease-Dependent Retrotranspositional Events Causing Human Genetic Disease: Mutation Detection Bias and Multiple Mechanisms of Target Gene Disruption

LINE-1 Hypomethylation in a Choline-Deficiency-Induced Liver Cancer in Rats: Dependence on Feeding Period

The ORF1 Protein Encoded by LINE-1: Structure and Function During L1 Retrotransposition

L1 Retrotransposons in Human Cancers