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Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.

ABSTRACT: Transposable elements (TEs) are prevalent repeats in the human genome, play a significant role in the regulome, and their disruption can contribute to tumorigenesis. However, TE influence on gene expression in cancer remains unclear. Here, we analyze 275 normal colon and 276 colorectal cancer samples from the SYSCOL cohort, discovering 10,231 and 5,199 TE-expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively, of which 376 are colorectal cancer specific eQTLs, likely due to methylation changes. Tumor-specific TE-eQTLs show greater enrichment of transcription factors, compared to shared TE-eQTLs suggesting specific regulation of their expression in tumor. Bayesian networks reveal 1,766 TEs as mediators of genetic effects, altering the expression of 1,558 genes, including 55 known cancer driver genes and show that tumor-specific TE-eQTLs trigger the driver capability of TEs. These insights expand our knowledge of cancer drivers, deepening our understanding of tumorigenesis and presenting potential avenues for therapeutic interventions.

SUBMITTER: Lykoskoufis NMR

PROVIDER: S-EPMC10811328 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.

Lykoskoufis Nikolaos M R NMR Planet Evarist E Ongen Halit H Trono Didier D Dermitzakis Emmanouil T ET

Nature communications 20240125 1

Transposable elements (TEs) are prevalent repeats in the human genome, play a significant role in the regulome, and their disruption can contribute to tumorigenesis. However, TE influence on gene expression in cancer remains unclear. Here, we analyze 275 normal colon and 276 colorectal cancer samples from the SYSCOL cohort, discovering 10,231 and 5,199 TE-expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively, of which 376 are colorectal cancer specific eQTLs, likel ...[more]

PMID: 38272908

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Project description:BackgroundTransposable elements (TE) make up a large portion of many plant genomes and are playing innovative roles in genome evolution. Several TEs can contribute to gene regulation by influencing expression of nearby genes as stress-responsive regulatory motifs. To delineate TE-mediated plant stress regulatory networks, we took a 2-step computational approach consisting of identifying TEs in the proximity of stress-responsive genes, followed by searching for cis-regulatory motifs in these TE sequences and linking them to known regulatory factors. Through a systematic meta-analysis of RNA-seq expression profiles and genome annotations, we investigated the relation between the presence of TE superfamilies upstream, downstream or within introns of nearby genes and the differential expression of these genes in various stress conditions in the TE-poor Arabidopsis thaliana and the TE-rich Solanum lycopersicum.ResultsWe found that stress conditions frequently expressed genes having members of various TE superfamilies in their genomic proximity, such as SINE upon proteotoxic stress and Copia and Gypsy upon heat stress in A. thaliana, and EPRV and hAT upon infection, and Harbinger, LINE and Retrotransposon upon light stress in S. lycopersicum. These stress-specific gene-proximal TEs were mostly located within introns and more detected near upregulated than downregulated genes. Similar stress conditions were often related to the same TE superfamily. Additionally, we detected both novel and known motifs in the sequences of those TEs pointing to regulatory cooption of these TEs upon stress. Next, we constructed the regulatory network of TFs that act through binding these TEs to their target genes upon stress and discovered TE-mediated regulons targeted by TFs such as BRB/BPC, HD, HSF, GATA, NAC, DREB/CBF and MYB factors in Arabidopsis and AP2/ERF/B3, NAC, NF-Y, MYB, CXC and HD factors in tomato.ConclusionsOverall, we map TE-mediated plant stress regulatory networks using numerous stress expression profile studies for two contrasting plant species to study the regulatory role TEs play in the response to stress. As TE-mediated gene regulation allows plants to adapt more rapidly to new environmental conditions, this study contributes to the future development of climate-resilient plants.

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Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.

Publications

Transposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer.

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