Estecio MR, Gallegos J, Vallot C et al.Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. Genome Res 20:1369-1382

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Genome Research (Impact Factor: 14.63). 10/2010; 20(10):1369-82. DOI: 10.1101/gr.107318.110
Source: PubMed


Epigenetic silencing plays an important role in cancer development. An attractive hypothesis is that local DNA features may participate in differential predisposition to gene hypermethylation. We found that, compared with methylation-resistant genes, methylation-prone genes have a lower frequency of SINE and LINE retrotransposons near their transcription start site. In several large testing sets, this distribution was highly predictive of promoter methylation. Genome-wide analysis showed that 22% of human genes were predicted to be methylation-prone in cancer; these tended to be genes that are down-regulated in cancer and that function in developmental processes. Moreover, retrotransposon distribution marks a larger fraction of methylation-prone genes compared to Polycomb group protein (PcG) marking in embryonic stem cells; indeed, PcG marking and our predictive model based on retrotransposon frequency appear to be correlated but also complementary. In summary, our data indicate that retrotransposon elements, which are widespread in our genome, are strongly associated with gene promoter DNA methylation in cancer and may in fact play a role in influencing epigenetic regulation in normal and abnormal physiological states.

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Available from: Jaroslav Jelinek, Oct 05, 2015
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    • "The strongest association of class I transposable elements with gene duplication is found within 5–10 kb distance from the respective genes [41]. In fact, there is evidence for duplication of such 5–10 kb regions for another class of chemosensory receptor genes [42]. "
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    ABSTRACT: Background Chemical senses are one of the foremost means by which organisms make sense of their environment, among them the olfactory and gustatory sense of vertebrates and arthropods. Both senses use large repertoires of receptors to achieve perception of complex chemosensory stimuli. High evolutionary dynamics of some olfactory and gustatory receptor gene families result in considerable variance of chemosensory perception between species. Interestingly, both ora/v1r genes and the closely related t2r genes constitute small and rather conserved families in teleost fish, but show rapid evolution and large species differences in tetrapods. To understand this transition, chemosensory gene repertoires of earlier diverging members of the tetrapod lineage, i.e. lobe-finned fish such as Latimeria would be of high interest. Results We report here the complete T2R repertoire of Latimeria chalumnae, using thorough data mining and extensive phylogenetic analysis. Eighty t2r genes were identified, by far the largest family reported for any species so far. The genomic neighborhood of t2r genes is enriched in repeat elements, which may have facilitated the extensive gene duplication events resulting in such a large family. Examination of non-synonymous vs. synonymous substitution rates (dN/dS) suggests pronounced positive Darwinian selection in Latimeria T2Rs, conceivably ensuring efficient neo-functionalization of newly born t2r genes. Notably, both traits, positive selection and enrichment of repeat elements in the genomic neighborhood, are absent in the twenty v1r genes of Latimeria. Sequence divergence in Latimeria T2Rs and V1Rs is high, reminescent of the corresponding teleost families. Some conserved sequence motifs of Latimeria T2Rs and V1Rs are shared with the respective teleost but not tetrapod genes, consistent with a potential role of such motifs in detection of aquatic chemosensory stimuli. Conclusions [bullet] The singularly large T2R repertoire of Latimeria may have been generated by facilitating local gene duplication via increased density of repeat elements, and efficient neofunctionalization via positive Darwinian selection. [bullet] The high evolutionary dynamics of tetrapod t2r gene families precedes the emergence of tetrapods, i.e. the water-to-land transition, and thus constitutes a basal feature of the lobe-finned lineage of vertebrates.
    BMC Genomics 08/2014; 15(1). DOI:10.1186/1471-2164-15-650 · 3.99 Impact Factor
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    • "Since REs are involved in reprogramming of DNA methylation (41,42), we investigated whether REs affected lincRNA methylation patterns. We quantified the REs around the TSSs of lincRNAs using the RMSK data from UCSC Genome Browser (43). "
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    ABSTRACT: Despite growing consensus that long intergenic non-coding ribonucleic acids (lincRNAs) are modulators of cancer, the knowledge about the deoxyribonucleic acid (DNA) methylation patterns of lincRNAs in cancers remains limited. In this study, we constructed DNA methylation profiles for 4629 tumors and 705 normal tissue samples from 20 different types of human cancer by reannotating data of DNA methylation arrays. We found that lincRNAs had different promoter methylation patterns in cancers. We classified 2461 lincRNAs into two categories and three subcategories, according to their promoter methylation patterns in tumors. LincRNAs with resistant methylation patterns in tumors had conserved transcriptional regulation regions and were ubiquitously expressed across normal tissues. By integrating cancer subtype data and patient clinical information, we identified lincRNAs with promoter methylation patterns that were associated with cancer status, subtype or prognosis for several cancers. Network analysis of aberrantly methylated lincRNAs in cancers showed that lincRNAs with aberrant methylation patterns might be involved in cancer development and progression. The methylated and demethylated lincRNAs identified in this study provide novel insights for developing cancer biomarkers and potential therapeutic targets.
    Nucleic Acids Research 07/2014; 42(13). DOI:10.1093/nar/gku575 · 9.11 Impact Factor
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    • "Thus, retrotransposons may well be more ubiquitous than DNA in the mammalian genomes. It has been reported that retrotransposons are capable of retrotransposition in various primate genomes and thus they have a major impact on the architecture and fluidity of their host genomes (Cordaux et al. 2006; Estécio et al. 2010; Nekrutenko and Li 2001). "
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    ABSTRACT: Mobile genetic elements are responsible for half of the human genome, creating the host genomic instability or variability through several mechanisms. Two types of abnormal DNA methylation in the genome, hypomethylation and hypermethylation, are associated with cancer progression. Genomic hypermethylation has been most often observed on the CpG islands around gene promoter regions in cancer cells. In contrast, hypomethylation has been observed on mobile genetic elements in the cancer cells. It is recently considered that the hypomethylation of mobile genetic elements may play a biological role in cancer cells along with the DNA hypermethylation on CpG islands. Growing evidence has indicated that mobile genetic elements could be associated with the cancer initiation and progression through the hypomethylation. Here we review the recent progress on the relationship between DNA methylation and mobile genetic elements, focusing on the hypomethylation of LINE-1 and HERV elements in various human cancers and suggest that DNA hypomethylation of mobile genetic elements could have potential to be a new cancer therapy target in the future.
    Genes & genomics 06/2013; 35(3). DOI:10.1007/s13258-013-0095-3 · 0.60 Impact Factor
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