Article

Altruistic functions for selfish DNA

Roslin Institute, University of Edinburgh, Roslin, Scotland, UK.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 10/2009; 8(18):2895-900. DOI: 10.4161/cc.8.18.9536
Source: PubMed

ABSTRACT

Mammalian genomes are comprised of 30-50% transposed elements (TEs). The vast majority of these TEs are truncated and mutated fragments of retrotransposons that are no longer capable of transposition. Although initially regarded as important factors in the evolution of gene regulatory networks, TEs are now commonly perceived as neutrally evolving and non-functional genomic elements. In a major development, recent works have strongly contradicted this "selfish DNA" or "junk DNA" dogma by demonstrating that TEs use a host of novel promoters to generate RNA on a massive scale across most eukaryotic cells. This transcription frequently functions to control the expression of protein-coding genes via alternative promoters, cis regulatory non protein-coding RNAs and the formation of double stranded short RNAs. If considered in sum, these findings challenge the designation of TEs as selfish and neutrally evolving genomic elements. Here, we will expand upon these themes and discuss challenges in establishing novel TE functions in vivo.

Full-text

Available from: Piero Carninci, Dec 14, 2013
www.landesbioscience.com Cell Cycle 2895
Cell Cycle 8:18, 2895-2900; September 15, 2009; © 2009 Landes Bioscience
EXTRA VIEW
EXTRA VIEW
Key words: retrotransposon, transposed
element, transcription, promoter, gene
expression, transcriptome
Submitted: 07/15/09
Accepted: 07/16/09
Previously published online:
www.landesbioscience.com/journals/cc/
article/9536
Correspondence to:
Geoffrey J. Faulkner and Piero Carninci; Email:
geoff.faulkner@roslin.ed.ac.uk and carninci@riken.
jp
M
ammalian genomes are comprised
of 30–50% transposed elements
(TEs). The vast majority of these TEs
are truncated and mutated fragments of
retrotransposons that are no longer capa-
ble of transposition. Although initially
regarded as important factors in the evo-
lution of gene regulatory networks, TEs
are now commonly perceived as neutrally
evolving and non-functional genomic
elements. In a major development, recent
works have strongly contradicted this
selfish DNA” or “junk DNA” dogma
by demonstrating that TEs use a host
of novel promoters to generate RNA on
a massive scale across most eukaryotic
cells. This transcription frequently func-
tions to control the expression of protein-
coding genes via alternative promoters,
cis regulatory non protein-coding RNAs
and the formation of double stranded
short RNAs. If considered in sum, these
findings challenge the designation of TEs
as selfish and neutrally evolving genomic
elements. Here, we will expand upon
these themes and discuss challenges in
establishing novel TE functions in vivo.
Transposed Elements:
Not Junk DNA?
The difference between transposable
and transposed elements is a simple and
yet important distinction in genetics.
Transposable elements—transposons and
retrotransposons that are capable of trans-
position—were first designated as “con-
trolling elements” in maize by Barbara
McClintock more than fty years ago
1
and have since been studied extensively
in mammalian systems. Their exclusive
expression in germ line and cancer cells
2
has been associated with numerous human
diseases, usually due to novel insertions
across protein-coding exons.
3-5
This pro-
pensity towards disruption likely explains
why mechanisms such as DNA methyla-
tion and endogenous RNA interference
have evolved to limit the activity of trans-
posable elements in mammals.
6-8
In contrast, there are more than three
million transposed elements (TEs) in the
human genome, derived primarily from
Long Interspersed Nuclear Elements
(LINEs), Short Interspersed Nuclear
Elements (SINEs), Long Terminal Repeats
(LTRs) and DNA transposons. Altogether
these elements contribute approximately
50% of our DNA.
9
TEs are, in almost all
cases, truncated and mutated copies of
transposable elements that have been ren-
dered immobile. For this reason, and for
their apparent lack of other functions, TEs
have been perceived in recent decades as
junk DNA” or “selfish DNA.
10
In a crucial experiment supporting this
view, Nobrega and colleagues removed two
megabase regions of non protein-coding
genomic DNA, including numerous TEs,
from an inbred mouse strain.
11
No phe-
notypic effects or changes in neighboring
gene expression were observed, at least in a
controlled laboratory setting free of patho-
gens or a full range of environmental chal-
lenges. It should also be noted that many
protein-coding gene knock out experi-
ments also lack an obvious phenotype,
with changes only revealed in very specific
conditions or upon the knock out of addi-
tional protein-coding genes.
12
Caution is
therefore necessary when analyzing nor-
mal phenotypes produced by non protein-
coding DNA knock out experiments.
11
Nonetheless, the recent Encyclopedia
of DNA Elements (ENCODE) pilot proj-
ect, one of the largest genome annotation
Altruistic functions for selfish DNA
Geoffrey J. Faulkner
1
and Piero Carninci
2
1
Roslin Institute; University of Edinburgh; Roslin, Scotland UK;
2
Omics Science Center; RIKEN Yokohama Institute; Yokohama, Kanagawa Japan
Page 1
2896 Cell Cycle Volume 8 Issue 18
switching on promoters would almost cer-
tainly involve transcribed TEs. As noted
earlier, most TE transcription is tissue-
specific; at rst glance we would there-
fore expect transcription ripples traveling
outwards to be in the main dampened by
TE promoters. However, as TEs tend to
be coexpressed with nearby genes in many
cases they would allow the transcription
ripple to continue outwards.
Ultimately, transcribed TEs may regu-
late specific genes but they also form a part
of a broader genomic landscape. In partic-
ular, transcribed TEs can affect the open-
ness of chromatin,
31
as well as the general
three dimensional structure of DNA. To
our knowledge, interactions between TEs
and other genomic elements are yet to
be examined in detail by Chromosome
Capture Conformation (3C), a strategy
designed to detect interactions between
different chromosomal regions.
32,33
We
believe that future studies will map these
interactions, as TEs are actively transcribed
and are likely to influence transcriptional
activation and repression at this level.
Hypoconservation of Transcribed
Transposed Elements
Sequence conservation is a widely used
measure of functional significance.
13
This
relationship is however far less useful for
TEs because it is common for a given
transposable element family to be specific
to a small taxonomic clade. Even across
the mammalian lineage TE content varies
widely.
34
For example, Alu SINEs account
for approximately 10% of the human
genome and, although derived from the
same ancestor (7SL RNA) as many other
SINES, are found only in primates.
9,35
Transposable elements may also transfer
horizontally amongst mammals.
36
For
these reasons it is difficult to place a value
on sequence conservation when applied to
deducing functional roles for TEs.
Compounding this situation is recent
evidence that point mutations may actu-
ally serve to activate transcription start
sites within TEs.
17, 37
In a recent study,
we found a degenerate mammalian ini-
tiator dinucleotide (AGT/G) was over-
whelmingly used by internal promoters in
immobile TEs, with a complete lack of the
CG initiator dinucleotides found for most
Rather than the TE being exapted by
the gene, it may then be more appropri-
ate to say that the gene has been exapted
by the TE. Even if the duplicated gene
is accompanied by its core promoter
22
or
internal regulatory circuitry,
23
it can even-
tually become tightly coexpressed with
the TE (Fig. 1), as we recently observed
for thousands of mammalian genes.
17
In
this manner, a gene is duplicated, inserted
elsewhere in the genome and regulated
differently to its ancestral paralog due to
the presence of TEs. This can be consid-
ered as a prime mechanism of transcrip-
tome evolution and expression divergence
between paralogs.
Conversely, when a TE is inserted in
the anking or intronic regions of a gene
it is subject to the same regulatory envi-
ronment that is already present and con-
trolling the gene. We can speculate that,
as most TE transcription is tissue specific
17
and most genes are not transcribed in a tis-
sue specific manner,
24
this second scenario
is less likely to induce a drastic change in
gene expression than the first scenario.
This would be particularly the case for
TEs that have retained their canonical
promoters; we have demonstrated else-
where that for most cells these promoters
produce far less RNA than other promot-
ers found in TEs.
17
In either scenario, however, the TE
and gene will in most cases at least par-
tially overlap in expression. The TE can
therefore impact upon transcription of the
gene via regulatory non protein-coding
RNAs (ncRNAs),
25,26
by providing an
alternative promoter
27
and by generating
antisense transcripts.
28
These events occur
frequently, as there is a strong enrichment
for TE transcription proximal to protein-
coding genes (Fig. 2)
17
one reason why
the removal of large intergenic regions can
have little impact upon phenotype.
11
Paired interactions between TEs and
genes are a major outcome of TE enrich-
ment in gene forests,
29
or clusters, but are
certainly not the only possibility. Recently,
Ebisuya and colleagues noted a ripples of
transcription phenomenon where entire
gene forests were activated after a gene
in a cluster became highly expressed in
response to growth factor stimulation.
30
A wave of transcription propagating
throughout a gene forest by sequentially
efforts to date, operated under the assump-
tion that ancient TEs were neutrally evolv-
ing and largely non-functional.
13
Far from
adhering to this nal view of all TEs, we
believe that until recently the right tools
were simply not available to test an alter-
native hypothesis—that many TEs have
important regulatory functions. Complete
mammalian reference genome sequences
and the development of massively paral-
lel sequencing technologies now allow us
to compare the genome and transcriptome
of an organism and evaluate the frequency
at which TEs regulate gene expression via
RNA intermediates.
Transposed Elements are Widely
Transcribed
Neither gene regulation by TEs, nor the
presence of tissue specific promoter ele-
ments in TEs, are new concepts.
14-16
However, novel technologies now allow
us to survey transcriptional activity on
a genome-wide level and elucidate wide-
spread gene regulatory functions for TEs.
Indeed, recent works discovered pervasive
transcription of most of the mammalian
genome using a large set of tissues,
13
with
an enrichment for tissue specific transcrip-
tion of TEs proximal to protein-coding
genes.
17
These observations allow us to propose
a subtle modification to the original model
postulated by Britten and Davidson
14
in
which repetitive DNA is quiescent until
activated by the insertion of a duplicated
gene. Rather, the components necessary to
initiate transcription, including transcrip-
tion factor binding sites
18
and enhancers
19
are present in TEs and direct transcription
at a low but tissue specific level.
17
If the TE
is subsequently exapted, or recruited to
serve a function, by the gene then purify-
ing selection
20
either silences or enhances
transcription of the TE.
19
Two scenarios create the basis for this
exaptation: (1) A gene is duplicated and
inserted next to a TE or (2) an active
transposable element inserts a truncated
TE next to or within a gene. In the rst
scenario, the gene is the new component
of the genomic region, rather than the
TE, and therefore the gene is predisposed
to control by the TE and any other dis-
tal regulatory elements that are present.
21
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www.landesbioscience.com Cell Cycle 2897
Detecting Transposed Element
Transcription
The high point mutation rate of tran-
scribed TEs provides a decisive advantage
in detecting their expression. Although
TEs are broadly defined as repetitive
DNA, they are made up of numerous
sub sequences that are unique on the
genome.
40
Unlike hybridization based
strategies,
41
sequence tag technologies
such as Cap Analysis Gene Expression
(CAGE)
42
and shotgun sequencing of
RNA (RNA-seq)
43,44
produce sufficient
resolution to reliably identify these unique
selected genomic sequences (Fig. 3) and
are less conserved than other TEs, regard-
less of their position relative to the near-
est protein-coding gene (Fig. 4). These
trends are also not due to bias in mapping
sequence tags to divergent TEs; very few
“young” TEs are expressed in somatic tis-
sues, as witnessed by a dearth of massively
multi-mapping sequence tags that map
to TEs.
40
We can therefore conclude that
there is a positive association between the
accumulation of point mutations in TEs
and TE expression.
mammalian genes.
24
One interpretation
of this observation is that weak initiator
dinucleotides are sufficient to generate
an effective cohort of regulatory RNAs.
Another interpretation is that point muta-
tions are required for strong CG initiator
elements present in TEsand controlled
by their associated promoter elements
to evade CpG methylation.
38,39
Therefore
a lack of TE conservation may actually
imply function.
This viewpoint is supported by evidence
that transcribed human TEs are hypocon-
servedacross the primate lineage in com-
parison to other TEs, exons and randomly
Figure 1. Possible mechanism for exaptation of a transcribed TE. (A) A ubiquitously expressed gene is duplicated and inserted next to a transcribed
and tissue specic TE and enhancer. The enhancer directs the expression of the TE. (B) The enhancer and transcribed TE direct the gene to become
gradually specic to the same tissue as the transcribed TE. Conversely, the regulatory machinery duplicated with the gene may have a weak effect upon
the transcription of the TE. (C) Regulation by the transcribed TE becomes essential for the gene to function in the most advantageous manner to the
host organism. The gene is now highly specic to the same tissue as, and controlled by, the transcribed TE.
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2898 Cell Cycle Volume 8 Issue 18
will likely prove to be of great utility in
the future.
A Wealth of Functional Trans-
posed Elements
Massively parallel short read sequencing
may reveal TE transcription and associated
characteristics such as tissue specificity,
exon structure and promoter architecture
but in most cases it is insufficient to con-
vincingly determine TE function. To dem-
onstrate novel functions for individual TEs
we must rely upon other functional genom-
ics techniques. Sequencing based methods
such as Rapid Amplification of cDNA
Ends (RACE)
46
and Sanger sequencing
of cDNAs and Expressed Sequence Tags
(ESTs), can detect and validate TE tran-
scription. Perhaps more importantly, these
techniques can also indicate whether a TE
generates a transcript that terminates in a
downstream gene on the same strand (an
alternative promoter) or on the opposite
strand (a natural antisense transcript).
28
In either case, TE transcription has great
potential to have a phenotypic effect
because transcription initiated in the TE
and controlled by the TE promoter physi-
cally overlaps and regulates protein-coding
Massively parallel sequence tag technolo-
gies can therefore be used to survey TE
transcription en masse, a concept that is
yet to be fully appreciated by the field but
sub sequences within individual TEs.
40
Sequence tag approaches also support bio-
informatic strategies to rescue” tags that
map to nearby non-unique sequences.
40,45
Figure 2. Distribution of TE transcription with respect to RefSeq genes for human (A) and mouse (B). Note that the cumulative curve is steepest
in the immediate anking regions of RefSeq genes for each major TE superfamily and that the steepness of the cumulative curve for all TEs is much
greater than that of non-TEs. RefSeq gene coordinates were downloaded from the UCSC Genome Browser (http://genome.ucsc.edu/). CAGE data
were mapped and processed as described previously.
17
Position “0” incorporates RefSeq exons and introns.
Figure 3. Sequence conservation for human RefSeq exons, TEs annotated to contain at least
one transcription start site,
17
all TEs and random genomic sequences. Conservation scores across
primates were extracted from the 44-way phyloP track at the UCSC Genome Browser (http://
genome.ucsc.edu/).
55
Note that the vast majority of TEs found in human are also found throughout
the primate lineage and that the most important aspect of this analysis is the relative conservation
of each category.
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26
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17
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26
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Figure 4. Transcribed human TEs are less conserved than other human TEs. TEs were classied
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17
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    • "All of this would seem to expose a cell to intolerable levels of retrotransposition, but would be safe in the context of a strictly regulated TSS. In contrast, when the retrotransposon sequence falls at the 3 0 end of a transcript, it appears to be targeted for repression [22]. Such transcripts pose a higher risk to genomic integrity, as they may contain all LTR sequences required for successful retrotransposition. "
    [Show abstract] [Hide abstract] ABSTRACT: Retrotransposons, the ancestors of retroviruses, have the potential for gene disruption and genomic takeover if not kept in check. Paradoxically, although host cells repress these elements by multiple mechanisms, they are transcribed and are even activated under stress conditions. Here, we describe a new mechanism of retrotransposon regulation through transcription start site (TSS) selection by altered nucleosome occupancy. We show that Fun30 chromatin remodelers cooperate to maintain a high level of nucleosome occupancy at retrotransposon-flanking long terminal repeat (LTR) elements. This enforces the use of a downstream TSS and the production of a truncated RNA incapable of reverse transcription and retrotransposition. However, in stressed cells, nucleosome occupancy at LTR elements is reduced, and the TSS shifts to allow for productive transcription. We propose that controlled retrotransposon transcription from a nonproductive TSS allows for rapid stress-induced activation, while preventing uncontrolled transposon activity in the genome.
    Preview · Article · Feb 2016 · EMBO Reports
    • "At the time, because no determined function could be correlated with this huge part of the chromatin, some termed this region as the dark matter. Further analysis showed that mobile DNA elements and their residues constitute a large portion (*45%) of the chromatin dark matter (Faulkner and Carninci, 2009). It appears that mobile DNA elements, which are also known as transposable elements (TEs), resided in eukaryotic genomes some 100 million years ago. "
    [Show abstract] [Hide abstract] ABSTRACT: Mobile DNA elements transposable elements (TEs) are genomic sequences capable of moving themselves independently into different parts of the genome. Viral invasion of eukaryotic genomes is assumed to be the main source of TEs. Selfish transposition of these elements could be a serious threat to the host cell, as they can insert themselves into the middle of coding genes and/or induce genomic instability. In response, through million years of evolution, cells have come up with various mechanisms such as genomic imprinting, DNA methylation, heterochromatin formation, and RNA interference to deactivate them. Interestingly, these processes have also greatly contributed to important cellular functions involved in cell differentiation, development, and differential gene expression. Propagation of TE copies during the course of evolution have resulted in increasing the genome size and providing proper space and flexibility in shaping the genome by creating new genes and establishing essential cellular structures such as heterochromatin, centromere, and telomeres. Yet, these elements are mostly labeled for playing a role in pathogenesis of human diseases. In this study, we attempt to introduce TEs as factors necessary for making us human rather than just selfish sequences or obligatory guests invading our DNA.
    No preview · Article · Jul 2015 · DNA and cell biology
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    • "Whatever may have been the mechanisms and processes that determined the positioning of SINEs, the resultant effect is that SINEs occupy different intergenic locations in the two genomes. It is well recognized that LINEs and SINEs can modulate the expression of genes in their vicinity by providing alternative promoters, splicing and polyadenylation sites and by heterochromatini- zation10111213. The absence of SINE1 in >80% of syntenic loci in the extant genomes of E. histolytica and E. dispar could result in differential expression of genes at these loci. This could profoundly influence the phenotype of the two species, which needs to be explored. "
    Full-text · Dataset · May 2015
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