Guanine quadruplexes are formed by specific regions of human transposable elements
- Matej Lexa†1,
- Pavlina Steflova†2,
- Tomas Martinek3,
- Michaela Vorlickova4, 5,
- Boris Vyskot2 and
- Eduard Kejnovsky2Email author
© Lexa et al.; licensee BioMed Central Ltd. 2014
Received: 18 August 2014
Accepted: 29 October 2014
Published: 27 November 2014
Transposable elements form a significant proportion of eukaryotic genomes. Recently, Lexa et al. (Nucleic Acids Res 42:968-978, 2014) reported that plant long terminal repeat (LTR) retrotransposons often contain potential quadruplex sequences (PQSs) in their LTRs and experimentally confirmed their ability to adopt four-stranded DNA conformations.
Here, we searched for PQSs in human retrotransposons and found that PQSs are specifically localized in the 3’-UTR of LINE-1 elements, in LTRs of HERV elements and are strongly accumulated in specific regions of SVA elements. Circular dichroism spectroscopy confirmed that most PQSs had adopted monomolecular or bimolecular guanine quadruplex structures. Evolutionarily young SVA elements contained more PQSs than older elements and their propensity to form quadruplex DNA was higher. Full-length L1 elements contained more PQSs than truncated elements; the highest proportion of PQSs was found inside transpositionally active L1 elements (PA2 and HS families).
Conservation of quadruplexes at specific positions of transposable elements implies their importance in their life cycle. The increasing quadruplex presence in evolutionarily young LINE-1 and SVA families makes these elements important contributors toward present genome-wide quadruplex distribution.
Transposable elements (TEs) are abundant inhabitants of eukaryotic genomes, representing e.g. about 50% of the human genome and up to 90% in some plant species. Long terminal repeat (LTR) retrotransposons are most common in plant genomes while animal genomes, including the human genome, are often flooded by non-LTR retrotransposons. Most of the human genome is transcribed and TEs therefore greatly contribute to cellular transcriptome and proteome [1, 2]. Recent insertions of TEs underlie the variability of human populations and can cause several human diseases [3, 4]. Somatic retrotranspositions occur during neuronal development [5, 6] and tumorigenesis . During the last two decades, it became widely accepted that TEs, as an inherently dynamic genome component, have an important role in both cell functioning  and genome evolution [9, 10].
Human LTR retrotransposons are represented by endogenous retroviruses (HERV) but their activity is currently very limited: most HERVs were inserted into the genomes of our ancestors earlier that 25 mya . LTR retrotransposons have LTR sequences at both ends, carry GAG and POL genes and several regulatory regions like promoter located inside LTR, primer binding site (PBS) and polypurine (PPT) sites where reverse transcription of the first and second strand of DNA starts, respectively. The majority of human TEs result from the present and past activity of non-LTR retrotransposons, including the LINE-1, Alu and SVA elements . LINE-1 (long interspersed element 1, or L1) have two ORFs coding for RNA binding protein (ORF1) and endonuclease and reverse transcriptase (ORF2). ORFs are flanked with 5’-UTR and 3’-UTR regions. There are at least 850,000 L1 copies in the human genome . Alu elements are about 300 bp long and have dimeric structure formed by the fusion of two monomers derived from 7SL RNA gene. Alus were active over the past 65 mya and the human genome contains more than 1 million copies. SVA elements are about 2 kb long and are composed of a hexamer repeat region, VNTR region, an Alu-like region, a HERV-K10-like region and polyadenylation signal ending with oligo(dA)-rich tail. SVAs were active throughout the last 25 mya of hominoid evolution and have about 3,000 copies . Both Alu and SVA are trans-mobilized by the L1 machinery .
Molecular processes participating in the retrotransposon life cycle are regulated both by enzymes encoded by these elements themselves and by several host factors. It is probable that the activity of retrotransposons can also be affected by the changes of DNA conformation that are known to influence many molecular processes (for review see ). Formation of multi-stranded DNA structures, namely quadruplex DNA, is probably involved in dimerization of the HIV-1 genomic RNA molecules found in virus particles . Similarly, long polypurine tract (PPT) located in 3’-UTR of L1 retrotransposons, where reverse transcription of the second cDNA strand starts, can form intrastrand quadruplex . Relationship between quadruplexes and transposons can be seen in the cleavage of quadruplexes by RAG1 protein during translocations in human lymphomas  because RAG1 protein evolved from transposase of the Transib family of DNA transposons .
Recently, we found  that potential quadruplex sequences (PQSs) are often located inside LTRs of plant LTR retrotransposons at specific distances from their promoter indicating a possible effect of quadruplexes on transcription. Quadruplexes were better preserved in evolutionary young elements which supports their functional role [20, 21]. Similar observation was made by Savage et al.  who found that younger human SVA elements contain more PQS sequences than older SVA elements but the ability of candidate sequences to adopt quadruplex conformation was not experimentally confirmed. Although quadruplexes were found in many regions of human genome, especially in promoters [23–25], systematic analysis of quadruplexes in all main types of human retrotransposons was lacking.
In this study, we searched for PQS sequences in human LINE-1, HERV, SVA and Alu elements. We analyzed the prominent regions of their location as well as the effect of element age and localization on chromosomes. The ability of candidate motifs to adopt quadruplex was verified by circular dichroism and gel electrophoresis.
Potential quadruplex-forming sequences are located in specific regions of human transposable elements
We analyzed the localization of PQSs inside main groups of human transposable elements (TEs), namely in LINE-1, Alu elements, HERV retrotransposons and SVA elements. We searched for the (G n X n G n X n G n X n G n ) motif representing potential G-quadruplex cluster inside 894,717 LINE-1 elements, 1,051,161 Alu elements, 38,578 HERV and 5,001 SVA elements or their fragments. Altogether, we found 264,711 PQS in all annotated repeats or their 200 bp flanking sequence (186,507 in plus strands, 78,204 in minus strands). Of those, 183,967 were associated with the four studied classes (136,977 in plus strands, 46,990 in minus strands).
Oligonucleotides used in this study
TAGGTGCTC GGGG TCA GGGG TCA GGGG TCA GGG ACCCACTTG
ATCACACTCT GGGG TGTTGT GGG T GGGGGG A GGGGGG AGGATAGCATT GGG AGATATACC
AAAGAGTCA GGG AA GGG AGATAA GGG T GGGG CCGTTTTAT
TAAATTGCT GGG CA GGGGGGG A GGG CTAGTCACG
GGAGATCAA GGG AAA GGGGG AGA GGG AGA GGG AGAGGCCAA
CGCCCGTCC GGG A GGG AGGT GGGGGGGG TCAGCCCCC
GGAGACCGT GGGG AGA GGG AGA GGG A GGGGG AGAGGAGAC
GCCCCGTCC GGG A GGG AGGT GGGGGGG TCAGCCCCC
GGAGAGAGA GGG AGA GGG AGA GGG AGA GGG AGA GGG AGAGTGCTG
GTGCCATCC GGG A GGG AGGT GGGGGGG TCAGCCCCC
CCAGCACTTT GGG AGGCC GGG T GGG T GGG TCACCTGAGG
CCAGCACTTT GGG A GGG T GGG T GGG TGGATCACTT
The abundance of PQSs in the neighborhood of transposable elements
The abundance of PQSs within transposable elements of different age and activity
We compared the PQS abundance in all LINE-1 elements, full-length LINE-1 and transcriptionally active LINE-1 families (L1HS and L1PA) . We found that full-length LINEs contained much more PQSs than truncated LINE elements (Figure 2a). Among full-length elements, the transcriptionally active L1HS and L1PA2 families contained more PQSs than was the average abundance of PQSs inside full-length LINEs. Truncated L1HS and L1PA2 homologues contained much less PQSs. These trends were observed both on autosomes and on X and Y sex chromosomes.We analyzed the abundance of PQSs inside SVA elements of different age - SVA-A (oldest family) to SVA-F (youngest family). We found that the abundance of PQSs was higher in younger elements (SVA-D, SVA-E and SVA-F) than in older elements (SVA-A, SVA-B and SVA-C) and this trend was same both in autosomes and sex chromosomes (Figure 2b). The abundance of PQSs was highest in middle-aged SVA elements (Figure 2b). The PQSs were common in the central part of elements in plus strand. Detailed analysis revealed that in older elements, the PQS abundance in the central part of plus strand decreased and predominated in the left part of SVA in the minus strand (not shown). The peak of PQSs in SVA-E present on the Y chromosome was caused by the low number of elements and the SVA-F elements even absented on the Y chromosome.
We made similar analysis of Alu elements where Alu-J are oldest, Alu-S are middle-aged and Alu-Y are youngest elements. We found that in contrast to LINE-1 and SVA, the age did not markedly affect the abundance of PQSs inside Alu elements. There is a slight PQS-increasing trend with age in the main families, however the youngest subfamilies (AluYg6, Ya5)  are also depleted of PQSs (Figure 2c). Because Alu elements have more PQSs in their vicinity than inside elements (Figure 3) we also analyzed the upstream and downstream regions. We found that older Alu elements contained more PQSs than younger elements in their downstream regions (Figure 2c). The PQS abundance did not differ markedly between autosomes and sex chromosomes, a small decrease in PQSs on the Y chromosome was registered (Figure 1d). The most active families of Alu (AluYg6 and AluYa5) had lower abundance of PQSs than average Alu-Y elements.
PQSs can form quadruplexes as revealed by circular dichroism
We probed DNA conformational properties of 12 oligonucleotides (Table 1) representing PQSs obtained from SVA, HERV, LINE-1 and Alu elements by circular dichroism (CD). We tested their ability to form quadruplex structures upon increasing concentration of potassium ions.
We found that potential quadruplex-forming sequences are located in specific regions of human transposable elements and experimentally verified the ability of such sequences to adopt quadruplex DNA conformation. Full-length and active L1 elements and younger SVA elements had a larger number of PQSs. The propensity of these sequences to form quadruplex and quadruplex stability (not shown) were higher than in older elements. Alu elements contained PQSs not inside but in their neighborhood where more PQSs were present in downstream regions of older elements.
Two available counts of G4-quadruplexes in the entire human genome found about 375,000 PQSs [24, 30]. This allows us to express our numbers as proportions of mobile element PQSs to whole-genome PQS content with a value of 71%. The four main classes of elements studied here carry 49% of total predicted PQSs. These numbers reflect the current human genome sequencing and annotation status and are very likely to miss potential PQSs in centromeres, telomeres or other difficult-to-map regions of the human genome.
Our results are in agreement with Savage et al.  who also found that the youngest SVA (SVA-E, SVA-F) contained more quadruplexes than older elements. Such age-dependent distribution of PQSs (Figure 2) can be explained by the action of constraints leading to fixation of quadruplexes in recent and active elements while non-active older elements accumulate mutations that hinder quadruplex formation. Moreover, we found that quadruplexes are present in the central part of SVA elements in plus strand and in the left part of minus strand. If the localization of quadruplexes in plus strand has negative effect on transcription and their presence in minus strand has a positive effect [15, 21], then the potential evolutionary balancing of quadruplexes abundance (an increase or a decrease) in complementary strands could regulate element activity over time.
The greater abundance of PQSs (that are GC-rich) in the neighborhood of older Alu elements is probably related to generally high GC-content of isochores containing older Alus . Surprisingly, despite the age-dependent increase of GC-content of Alu neighborhood, the abundance of PQSs inside Alu elements was very low (Figure 3) and did not increase with the element age (Figure 2).
We have shown that PQSs are strongly accumulated in 3’-UTR of LINE-1 elements. Quadruplexes located in 3’-UTR can have an effect on target-primed reverse transcription (TPRT) that starts at the 3’ end. Quadruplexes formed either by RNA template or by the growing first DNA strand can represent a barrier for reverse transcription. However, quadruplex DNA can regulate not only the transposable element itself but can also influence neighboring genes as was proposed recently by Kejnovsky and Lexa . Because SVA elements are preferentially located inside genes or in their neighborhood  we suggest that recent SVA elements could spread quadruplex motifs close to genes or into genes and in this way they regulate expression of these genes. The regulatory potential of quadruplexes inside TEs decreases as the element gets older and is eroded by mutations and rearrangements. In this way, quadruplexes can enlarge the potential of transposable elements to respond to environmental challenges as was suggested by McClintock  long time ago.
Quadruplexes carried by TEs can also affect other cellular processes like replication or epigenetic regulation. It is remarkable that quadruplexes are located close to the LINE-1 poly(dA) tail that represents the labile region of duplex DNA. Other labile (AT-rich) regions are represented by replication origins and, surprisingly, also here quadruplexes are located . Because quadruplexes also represent barriers for replication, or at least can slow it down, the spreading of PQSs by retrotransposons can also contribute to the regulation of replication speed. In addition, the quadruplexes can represent epigenetic marks in large introns that contain repetitive DNA and are also AT-rich [21, 34]. Moreover, if non-B DNA conformations are nucleosome-free [35, 36] and some transposable elements are preferentially inserted into naked DNA , then one would expect that such regions could represent sites for nested insertions, at least in some TE families.
Several proteins were shown to bind quadruplex DNA [15, 38]. For example, p53 protein, that has binding sites inside human Alu and L1 elements [39, 40], can strongly bind quadruplex DNA . Another example is the recombination and repair protein Ku70 that was shown to bind cDNA of Ty1 yeast retrotransposons  and has high affinity to quadruplex DNA . In this context, it is interesting that human LINEs have many Ku70/80 binding sites .
Taken together, the remarkable ability of some proteins to bind both TEs and quadruplex DNA underlining the relationship of these unusual DNA conformations with transposable elements as well as the higher abundance of PQSs inside younger, full-length and active elements indicates the role of quadruplexes in TE spreading. Such a role can consist in negative or positive regulation of TE activity, e.g. in response to current intracellular ionic conditions influencing the stability of quadruplexes. In the long-term perspective, quadruplexes can represent an evolutionary feedback suppressing non-controlled amplification of active elements.
The results suggest that activity of transposable elements, especially LINE-1 and SVA elements, contributes towards genome-wide quadruplex distribution in human. Conservation of quadruplexes at specific positions implies their function either in the life cycle of transposable elements or host genome maintenance, or both. All tested PQSs were able to form quadruplex structure in vitro, albeit with differing willingness, strand orientation and molecularity. LINE-1 and SVA families displayed an age-dependent pattern with younger elements containing a higher number of more stable quadruplexes. Further studies should be done to determine how the conserved elements are selected for during evolution.
Search for potential quadruplex-forming sequences inside transposable element
Repetitive sequences in the human genome were collected using UCSC Table Browser data . The repeats from Repeat Masker track  (RepeatMasker, www.repeatmasker.org) from the hg38 version of the human genome were extended 200 bp in both directions and exported from Table Browser in FASTA format. The header of each sequence contained the precise position of each sequence in the hg38 assembly of the human genome, including the harboring chromosome. It also identified the class and family of element by name as returned by Repeat Masker. These identifiers were used in assigning data and results to repeats, chromosomes or to calculate whether a detected feature was inside or outside the studied repetitive region. A feature was considered to be inside only if one of its ends localized to the TE proper (not the flanking region). This dataset also includes truncated or fragmented sequences. In selected analyses, we used full-length elements, using only TEs that were longer than two thirds of a typical representative, resulting in the following thresholds [given in bp]: L1 - 4,700, Alu - 250, SVA - 1,600, HERV (ltr) - 300, HERV (internal) - 2000.
The collected sequences were scanned for the occurrence of the typical PQS3 pattern GGG-N1-7-GGG-N1-7-GGG-1-7-GGG on both strands and labelled PQS3+ and PQS3-, respectively. The scan used a Perl script based on the regular expressions used in our previous study , recording the position and identity of each PQS3 pattern for subsequent counting and plotting. To verify that PQS frequency is not simply determined by the overall GC-content of the respective region, we calculated the expected number of PQSs in a random sequence generated by a second-order Markov model. This model was derived from the original sequence in windows of 150 bp as described previously [20, 23].
CD spectroscopy and polyacrylamide gel electrophoresis
High-quality oligonucleotides (lyophilized) were purchased from Generi Biotech (Hradec Králové, Czech Republic) and dissolved in 1 mM sodium phosphate buffer with 0.3 mM EDTA (pH 7.0) to obtain final stock concentration 100 OD.ml-1. Chemicals of analytical grade (Sigma-Aldrich) and deionized water (18 × 106 ohm resistance, Elga) were used for buffers. The exact oligonucleotide concentration was determined by absorbance measurements of appropriately diluted samples at 90°C in the above buffer using Unicam 5625 UV/VIS spectrophotometer and molar extinction coefficients calculated according to Gray et al. . Before any measurements the DNA samples were denatured for 2 min at 90°C and slowly cooled to room temperature.
CD measurements were done using a Jasco 815 dichrograph in 1 cm Hellma cells, placed in a temperature-controlled holder. Circular dichroism was expressed as the difference in the molar absorption of the left-handed and right-handed circularly polarized light, Δ ε in units of M-1cm-1. The molarities (M) were related to nucleosides. Experimental conditions were changed directly in the cells by adding concentrated solutions of potassium chloride and the final sample concentration was corrected for the volume increase. All the presented K+ dependences were measured at 20° and 1°C.
Native polyacrylamide gel electrophoresis was performed in a temperature-controlled electrophoretic apparatus (SE-600; HoeferScientific). The gel concentration was 16% (29:1 monomer to bis ratio; Applichem). Two micrograms of oligonucleotide dissolved in 10 mM potassium phosphate and 135 mM potassium chloride were loaded into each lane. Samples were electrophoresed in 70 mM concentration of K+ ions at 20°C for 18 h at 30V or at 1°C for 18 h at 55V. Gels were stained with Stains All (Sigma) after electrophoresis and scanned using the Personal Densitometer SI, model 375-A (Molecular Dynamics).
This work was supported by the Czech Science Foundation [grants P305/10/0930 to EK, P501/10/0102, P501/10/P483 to BV and P205/12/0466 to MV]; by the project "CEITEC - Central European Institute of Technology" [CZ.1.05/1.1.00/02.0068] from European Regional Development Fund; by the project OPVK [CZ.1.07/2.3.00/20.0045] and by the framework of the IT4Innovations Centre of Excellence project, [CZ.1.05/1.1.00/02.0070] supported by Operational Programme ’Research and Development for Innovations’.
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