Epigenetic activation of Genomic Retrotransposon

A Ahmed JournalMansour of Cell and Molecular Biology 6(2): 99-107, 2007 Review Article 99 Haliç University, Printed in Turkey. http://jcmb.halic.edu.tr Epigenetic activation of genomic retrotransposons Ahmed Mansour Agricultural Genetic Engineering, Genetics Department, Faculty of Agriculture, Zagazig University, Egypt. (author for correspondence; [email protected]) Received 18 September 2007; Accepted 04 December 2007 _____________________________________________________________________________________ Abstract Retrotransposons outnumber the genes in large plant genomes, thereby comprising the bulk of the genome. They are largely quiescent during development, but become more active under stress conditions. These elements spread throughout the genome by a process termed retrotransposition, which includes transcription of an element into RNA, reverse transcription into cDNA, and reinsertion of the copied element into a new genomic location. Biotic and abiotic stresses are regular phenomena facing plants. Likewise, both retrotransposons and retroviruses can be stress-activated. Activation of retrotransposable elements can be induced by various stresses. In particular, long terminal repeat (LTR) retrotransposons, which were found in most plant species, are characterized by a high level of variability in the LTR sequences involved in transcription, and have evolved by gaining new expression patterns mostly associated with responses to diverse stress stimuli. Most of the plant LTR retrotransposons produce larger pools of transcripts in response to biotic and abiotic stress. Recently it was shown that the epigenetic activation of these mobile elements alters the expression of adjacent genes. The new insertions in or next to coding regions generate mutations that can lead to changes in gene expression and reshape the genome, both structurally and functionally. Thus, activation of LTR retrotransposable elements can play an essential role in plant development and evolution. Key Words: Retrotransposon, transposition, stress activation, epigenetic activation, LTR Genomik retrotranspozonların epigenetik aktivasyonu Özet Retrotranspozonlar büyük bitki genomlarındaki genlerden sayıca fazladırlar, bu yüzden de genomun önemli bir bölümünü oluştururlar. Gelişim sürecinde çoğu zaman etkisiz olup, stres koşullarında etkin hale geçerler. Bu öğeler; RNA transkripsiyonu, cDNA ters transkripsiyonu ve kopyalanmış parçanın genomda yeni bir konuma yeniden eklenmesi aşamalarından oluşan retrotranspozisyon işlemi sayesinde genom boyunca yayılmışlardır. Biyotik ve abiyotik stresler bitkilerin sıkça karşılaştıkları durumlardır. Aynı şekilde, hem retrotranspozonlar hem de retrovirüsler stres yoluyla etkin hale geçebilirler. Retrotranspozlanabilir elementlerin aktivasyonu çeşitli stresler tarafından gerçekleştirilebilir. Özellikle birçok bitki türünde bulunan uzun uç tekrarlı (LTR) retrotranspozonlar, transkripsiyonda rol oynayan LTR dizilerindeki yüksek değişkenlik derecesi ile karakterize edilirler ve farklı stres uyarılarına cevap vermekle ilişkili yeni ekspresyon şekilleri kazanarak evrimleşmişlerdir. Bitki LTR retrotranspozonlarının birçoğu, biyotik ve abiyotik stres uyarılarına cevap olarak daha geniş transkript havuzları üretirler. Yakın bir zaman önce, bu hareketli elementlerin epigenetik aktivasyonunun bitişik genlerin ekpresyonunu etkilediği ortaya çıkartılmıştır. Kodlayan bölgelerde ya da yakındaki bir bölgedeki yeni dizi eklenmeleri, gen ifadesini değiştirecek ve genomu hem yapısal 100 A Ahmed Mansour hem de işlevsel olarak yeniden yapılandıracak mutasyonlara sebep olmaktadır. Bu yüzden, LTR retrotranspozlanabilir elementlerin aktivasyonu bitki gelişimi ve evriminde önemli bir rol oynayabilir. Anahtar Sözcükler: Retrotranspozon, transpozisyon, stres aktivasyonu, epigenetik aktivasyon, LTR ______________________________________________________________________________________ LTR retrotransposons widespread through genomes Retrotransposons are major genomic components of most eukaryotic organisms. The emerging data show that a significant portion of eukaryotic genomes is composed of transposable elements (TEs) (Jurka et al., 2007). In plants for example, they constitute 15% of the nuclear DNA in Arabidopsis thaliana, 50-80% of some grass genomes, and more than 90% in some Liliaceae (Feschotte et al., 2002; Sabot and Schulman, 2006). In human it represents nearly half (42%) of the human genome (IHGSC, 2001). LTR retrotransposons are the most abundant class of transposable elements in plants and are the main components of higher plant genomic DNA. As their name indicates, the LTR retrotransposons are flanked by LTRs. In addition, it is now well established that the differences in genome sizes observed in the plant kingdom are accompanied by variations in LTR retrotransposon content, suggesting that LTR retrotransposons might be important players in the evolution of plant genome sizes, along with polyploidy (Vitte and Panaud, 2005). They have a great impact in shaping their host genomes through insertional mutagenesis, gene expression changes and recombination (Kashkush et al., 2003). Stress impact on LTR and non-LTR retrotransposons Different stresses have been shown to influence many plant retrotransposons. For instance, various biotic and abiotic stresses are shown to increase expression of various transcriptionally active LTR retrotransposons include chilling, infection, mechanical damage, in vitro regeneration, hybridization and generation of doubled haploids (Hirochika, 1995; Grandbastien et al., 2005, Salazar et al., 2007). In plants, it has been reported that retrotransposons of rice were involved in mutations induced by tissue culture (Hirochika et al., 1996). Also, exposure to cell-wall hydrolases activates specific expression of retrotransposon in tobacco (Pouteau et al., 1991). In human cells, it was reported that human endogenous retrovirus (HERV) elements have been reported to be transactivated by viral infections. This transactivation by viral infection was shown in different cell-lines (Nellaker et al., 2006). On the other hand, non-LTR retrotransposons can also be activated by stress. Moreover, it was reported that cancer induces retrotransposable elements, long interspersed nuclear elements LINE-1(L1), in mammalian tissue cultures (Kuff and Lueders, 1988). Active retrotransposons in different species Most active retrotransposon families comprise several members and are dispersed throughout genomes (Cheng et al., 2006; Grandbastien, 1994; Grandbastien, 2004, Hagan and Rudin, 2002). A high variability in the nucleotide sequences as well as in different cis-acting elements have been determined when promoter regions from different family members were compared. In that way, different retrotransposon families can respond differently to specific stress challenges (Beguiristain et al., 2001). The ability of retrotransposons to respond to a wide variety of signal molecules is not a common feature between all retrotransposons. By surveying some induced retrotransposons under stress, it was evident that specific groups of retrotransposons are more likely to be activated by stress than others (Table 1). Tnt1 and Tto1 active retrotransposon in Solanaece In dicotyledon plants for instance, Tnt1A element, which is originally discovered in tobacco, is expressed in response to various stresses, such as wounding, biotic elicitors and pathogen attacks. However, it was shown that fungal extracts efficiently activate Tnt1 mobility (Melayah et al., 2001). These results indicate that activation by Epigenetic activation of retrotransposons A 101 Table 1. Description of some stress activated transposable elements. STRESS TYPE Tissue culture Cell-wall hydrolases Chilling Adenine starvation Wounding Protoplast preparation High salt concentrations Interspecific hybridization Adaptation to a moisture gradient Microbial Factors Mechanical damage In vitro regeneration Viral infection Cytosine demethylation UV light Resistance to bacterial blight and plant development Fungal infection Heat shock Viral infection Trichothecene mycotoxin deoxynivalenol (DON) Cold stress Environmental hydrocarbon Common chemotherapeutic drugs and gamma-radiation Hybridization and generation of doubled haploids Elements Element Type Tto1 , Tos17 Copia Tnt1 Tos17 Ty1 TLC1 TLC1 TLC1 Wis 2-1A Bare-1 Copia Copia Copia Copia Copia Copia Copia Copia Tnt1 Tnt1 Tnt1 Tos17 Tos17 Reme1 Copia Copia Copia Copia Copia Copia Tos17 Copia Grandbastien ,2004 Grandbastien et al 1997 Grandbastien et al 1998 Hirochika el al, 1995 Liu et al., 2004 Gyulai et al., 2008 Unpublished Data Sha et al., 2005 Romani PP and Erika LTR MAGGY HERV-W Gypsy Ansari et al., 2007 Retrotrasposonlike homologue LTR- Retrotransposon LINE-1 (L1) SINEs mPing microbial factors of pathogen origin can generate genetic diversity in plants (Grandbastien et al., 2005). This activation is mainly promoterdependent. It was reported that Tnt1A promoter has the potential to be activated by various biotic and abiotic stimuli. However, a number of these stimuli are specifically repressed in tobacco and are revealed only when the LTR promoter is placed in a heterologous context (Grandbastien et al., 1997). Other example for that is TLC1.1 retrotransposon family in Lycopersicon chilense. This retrotransposon can be activated in response to Gypsy-like LTRretrotransposon NA NA Non-LTR Retroposon Transposon MITEs References Hirochika el al, 1996 Liu et al., 2004 Pouteau, 1991 Hirochika, 1995 Todeschini et al., 2005 Tapia et al., 2005 Tapia et al., 2005 Tapia et al., 2005 Kashkush et al., 2002, 2003 Kalendar et al., 2000 Ikeda et al., 2001 Nellaker et al 2006 Dellaporta et al 1984 Ansari et al., 2007 Steward et al., 2002 Ivashuta et al., 2002 Stribinskis et al 2006 Hagan and Rudin , 2002 Hagan et al., 2003 Shan et al., 2005 diverse stress conditions such as wounding, protoplast preparation, and high salt concentrations. It is also transcriptionally induced in response to several stress-associated signaling molecules in vivo including ethylene, methyl jasmonate, salicylic acid, and 2,4-dichlorophenoxyacetic acid. Based on these results, it was suggested that ethylenedependent signaling is the main signaling pathway involved in the regulation of the expression of the TLC1.1 retrotransposon (Tapia et al., 2005). Recently, it was shown that the promoter of the TLC1.1 retrotransposon is also activated by multiple stress-related signaling molecules. In particu- A 102 Ahmed Mansour lar a 270 bp fragment (P270) derivative of this retroelement promoter, is able to activate the transcription of the GUS reporter gene in transgenic plants in response to salicylic acid (SA), abscisic acid (ABA), methyl jasmonate (MeJA), hydrogen peroxide (H2O2) and the synthetic auxin 2,4-D (Salazar et al., 2007). Moreover, it was also shown in Solanaecea that linear DNA intermediates of Tto1 retrotransposon accumulates in Gag particles in stressed tobacco. The accumulation of Tto1 linear DNA molecules in particle fractions were detected from callus and methyl jasmonate-treated leaves of tobacco, but not from non-stressed leaves (Takeda et al., 2001). is strongly activated by gamma-irradiation and this activation of transposition rises with increasing doses of gamma-rays and is stronger for Ty1 elements than for the related Ty2 elements. A moderate increase in Ty1 cDNA levels was also observed, indicating that ionizing radiation can induce the synthesis of Ty1 cDNA. In the same report, Ty1 RNA levels are markedly elevated upon irradiation; however, no significant increase of TyA1 protein was detected (Sacerdot et al., 2005). In a similar report, it was shown that Ty1 transcription is stimulated under severe adenine starvation conditions and activation mechanism involves chromatin remodeling at Ty1 promoters (Todeschini et al., 2005). Active retrotransposons in cereals Stress activation of non-LTR retrotransposon in mammalian cells In monocots, Tos17, copia-like retrotransposon of rice, was shown to be activated by different biotic and abiotic stresses such as tissue culture, cytosine demethylation, development and pathogen induction (Liu et al., 2004, Sha et al., 2005). It was shown that the adult plant resistance to bacterial blight as well as development are related to activation and polymorphism of Tos17. In other report, activation of a rice endogenous retrotransposon Tos17 was shown in tissue culture accompanied by cytosine demethylation and causes heritable alteration in methylation pattern of the flanking genomic regions (Liu et al., 2004). In wheat, it was reported that activation of Wis2-1A retrotransposon transcripts in a newly synthesized wheat amphiploid derives from an interspecific hybridization followed by chromosome doubling (Kashkush et al., 2002, 2003). This activation indicates an evolutionarily important role of Wis 2-1A retrotransposon in wheat development. Ty family, an active LTR-retrotransposons in yeast LTR-retrotransposons found in unicellular organisms such as yeast, Saccharomyces cerevisiae, are also activated by stress (Sacerdot et al., 2005; Todeschini et al., 2005). Ty1 elements in yeast are shown to be activated by genetic and environmental stress. Several DNA-damaging agents are proved to increase both Ty1 transcription and retrotransposition (Lesage and Todeschini, 2005). For instance, it was found that Ty1 transposition In mammalian, approximately one-quarter of the human genome is composed of short and long interspersed elements (non LTR transposons such as SINEs and LINEs, respectively). Long interspersed nuclear elements (L1) are abundant retrotransposons and usually remain silent under most conditions. Cellular stress signals activate L1 and it was shown that exposing cells to reactive carcinogenic intermediates increases L1 retrotransposition in HeLa cells (Stribinskis and Ramos, 2006). Recombination events involving these elements, including novel insertions into active genes, have been associated with a number of human diseases. Several common chemotherapeutic drugs and gamma radiation have been show to be associated with dramatic induction of SINE transcription, and of a concomitant endogenous reverse transcriptase activity (Hagan and Rudin, 2002). In another report, it was shown that HERV-W elements, including elements lacking regulatory LTRs, are expressed in cell-specific patterns and can be modulated and induced by many environmental influences (Nellaker et al., 2006). It was shown to be associated with schizophrenia, multiple sclerosis, preeclampsia and infections by influenza viruses. Retrotransposon responses differ among different host genotypes Many reports have been shown that the retrotransposon responses may differ between different host genotypes. For instance, Gypsy-like transposable elements such Erika and Romani PP, were up- Epigenetic activation of retrotransposons regulated in wheat heads in response to fungal mycotoxin stress. The trichothecene mycotoxin deoxynivalenol (DON) induced accumulation of retrotransposon and functionally uncharacterized transcript homologs in wheat root tissue. As with disease symptoms, transcript accumulation in wheat heads was generally higher in response to wild-type GZ3639 than to mutant GZT40 (up to 1.7 times higher) (Ansari et al., 2007). Also, it has been reported that the heritable alteration in cytosine-methylation patterns occurred in some regions flanking retroelement in some rice line and not to others (Liu et al., 2004). Moreover, the activity of Tos17 was different in three rice lines (the parental line cv. Matsumae and two introgression lines, RZ2 and RZ35) in response to tissue culture. This may be due to the fact that each line harbors different copies of the element. But it was shown that only in introgression line RZ35, Tos17 was transcriptionally activated and temporarily mobilized by tissue culture, which was followed by repression before or upon plant regeneration (Liu et al., 2004). In alfalfa (Medicago sativa), Ivashuta et al. (2002) found repetitive elements carrying long-terminal repeats (LTR) and other retroelement-like features showing strong expression under low temperatures and also demonstrating dramatic differences in expression between different alfalfa varieties. This different behavior of plant retrotransposon in ‘‘natural host’’ versus expression in heterologus species has been also described for the tobacco Tnt1 retroelement (Granbastien et al., 2005). Tnt1 retrotransposon, which is found in various Solanaceae species, are characterized by a high level of variability in the LTR sequences involved in transcription. It was reported that the behavior of Tnt1 retrotransposons differs between host specie. Granbastien et al. (2005) have proposed that this is most probably in correlation to differences in expression conditions in the evolutionary and environmental history of each host. Thus, retrotransposon responses may differ between host genotypes. These specificities that differ sensibly for each genotype, possibly reflecting an adaptive response of ancestral populations to different stimuli. It would be interesting to conduct a more in depth analysis of the effect of different stress treatments on epigenetic regulation and retrotransposon activity in different plant genotypes. A 103 LTRs insertions lead to changes in gene expression and phenotypic diversity Retroelements are important sources of plant genetic diversity (Kumar and Bennetzen, 1999). LTRs insertions in or next to coding regions generate mutations that can lead to changes in gene expression. For example, TntlA transposition preferentially targets genic regions, suggesting that the activity of transposable elements can modulate genic functions and represent a natural source of phenotypic diversity (Granbastien et al., 2005). Furthermore, run-off transcription from LTRs can lead to overexpression or suppression of nearby genes. For instance, it was reported that activation of antisense or sense transcripts of Wis2-1A retrotransposon in wheat is associated with silencing or activation of the corresponding genes, respectively (Kashkush et al., 2002, 2003). Moreover it was shown in maize that the activity of the element can in turn affect neighboring genes. This is shown for an Spm insertion in the a locus (Masson, et al., 1987) and a Mu insertion in hcf106 gene (Martienssen et al., 1990), but the mechanisms by which this occurs are not well understood. Hence, retrotransposons can be potential controlling elements in the genome because of their abundance in genomes and their ability to be activated by various signals. Genomic controlling mechanisms for retrotransposon activity The level of LTR retrotransposon expression, even following stress induction, is shown to be generally much lower than for ‘classical’ genes (Wessler, 1996). That was reasoned due to the LTR itself being a weak promoter, or due to transcriptional or post-transcriptional repression, with possible mechanisms including methylation, heterochromatin formation and RNA interference (RNAi) (Okamoto and Hirochika, 2001). In fact, transposable elements represent a threat to the integrity of their host genomes because of their mutagenic potential (Kidwell and Lisch, 2000). Thus host genomes have developed mechanisms to control the activity of the TEs and their mutagenic potential (Vicient et al. 1999; Jensen et al. 1999; Hirochika et al. 2000). The most general and effective mechanism is probably the silencing mechanism (Figure 1). Posttranscriptional gene silencing (PTGS) mediated by short interfering RNA (siRNA) and promoter inactivation by methylation (transcriptional gene silenc- A 104 Ahmed Mansour ing, TGS) are very effective silencing mechanisms (Vance and Vaucheret, 2002; Cheng et al., 2006). Although they are usually inactive, some retrotransposon can escape silencing (Figure1). Thus there are few plant retrotransposons that have maintained their ability to transpose and are activated only under stress situations (Kumar and Bennetzen, 1999). Active retrotransposons contain active promoters McClintock (1984) proposed the genomic shock model which postulates that mobile genetic elements play a crucial role in plant genome reorganization induced by environmental challenges. Based on this theory, promoters of active LTR retrotransposons should contain cis-regulatory elements necessary to respond to signaling pathways related to the defense system. Recently it was shown that a common characteristic of most active plant retrotransposons is that they all contain cis-regulatory elements in their promoter (U3 region of LTR 5′) associated to signal transduction pathways related to plant defense response (Salazar et al., 2007)(Figure 1). In fact, active retrotransposons are switched on by stress and their promoter elements are similar to those of plant defense genes, and it may bind to similar defense-induced transcription factors (Casacuberta and Santiago, 2003). Recruitment of solo LTRs containing stress response elements to roles as Figure 1. Proposed scheme for stress activation of retrotransposon. cellular promoters may provide a ready coordinating system for coping with stress. Numerous endogenous stress promoters share strong sequence similarities with LTRs (White et al., 1994; Dunn et al., 2006) (Figure 1). Transposition and genetic diversity Different kinds of stresses trigger different signaling pathways specific for each stress. Despite different interactions between signaling pathways, they usually differentiate at the end. Many cellular stress signals activate the retrotransposons (Grandbastien et al., 1998), but the molecular mechanisms controlling the activation of retrotransposons remain unclear. Retrotransposon may benefit from stress conditions, because it may be difficult for the plant to simultaneously silence transcription of the retrotransposon and maintain the defensive response. This activation may be due to the regulatory sequences involved in this activation are similar in various stressresponsive plant genes (Grandbastien, 2004). They insert themselves at different positions in host genomes thus they can be important sources of genetic diversity and evolution (Beguiristain et al., 2001; Casacuberta and Santiago, 2003). Summary and conclusions In summary, LTR retrotransposons which are the most abundant mobile elements in the genome seems to play an important role in genome reorgan- Epigenetic activation of retrotransposons ization induced by environmental challenges. Based on the above mentioned reports, the environmental stresses cause an epigenetic activation of mobile elements, with or without LTR, dispersed throughout the genome. Despite of the restrict silencing mechanisms; few retrotransposons in each genome have maintained their ability to transpose and activate under stress situations. It has been clearly shown that retrotransposons can be expressed in specific patterns which can be modulated by different environmental influences. This brings into light that mechanisms behind the regulation and expression of the retroelements are more complex than previously assumed and suggest biological functions of these transcripts. The success of retro-elements in this function depends on the ability of their promoters to respond to different signaling pathways that regulate plant adaptation to biotic and abiotic stresses. This strengthens the hypothesis that stress modulation of transposable elements might play a role in generating host genetic plasticity in response to environmental stresses. Reviewing the available experimental results suggests that, despite that there are clear examples of mutations and retrotransposon movements induced by external factors, environmental stress or introduction of foreign material into a genome does not cause drastic genomic changes. 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