scholarly journals Role of Transposable Elements in Gene Regulation in the Human Genome

2021 ◽  
Author(s):  
Arsala Ali ◽  
Kyudong Han ◽  
Ping Liang
Keyword(s):  
Gene Regulation ◽  
Transposable Elements ◽  
Regulatory Sequences ◽  
Rna Sequences ◽  
Expression Of Genes ◽  
Wide Range ◽  
Lineage Specificity ◽  
Regulatory Rnas ◽  
Potential Factors ◽  
Interspersed Repeats

Transposable elements (TEs), also known as mobile elements (MEs), are interspersed repeats that constitute a major fraction of the genomes of higher organisms. As one of their important functional impacts on gene function and genome evolution, TEs participate in regulating the expression of genes nearby and even far away at transcriptional and post-transcriptional levels. There are two known principal ways by which TEs regulate expression of genes. First, TEs provide cis-regulatory sequences in the genome with their intrinsic regulatory properties for their own expression making them potential factors for regulating the expression of the host genes. TE-derived cis-regulatory sites are found in promoter and enhancer elements, providing binding sites for a wide range of trans-acting factors. Second, TEs encode for regulatory RNAs with their sequences showed to be present in a substantial fraction of miRNAs and long non-coding RNAs (lncRNAs), indicating the TE origin of these RNAs. Furthermore, TEs sequences were found to be critical for regulatory functions of these RNAs including binding to the target mRNA. TEs thus provide crucial regulatory roles by being part of cis-regulatory and regulatory RNA sequences. Moreover, both TE-derived cis-regulatory sequences and TE-derived regulatory RNAs, have been implicated to provide evolutionary novelty to gene regulation. These TE-derived regulatory mechanisms also tend to function in tissue-specific fashion. In this review, we aim to comprehensively cover the studies regarding these two aspects of TE-mediated gene regulation, mainly focusing on the mechanisms, contribution of different types of TEs, differential roles among tissue types, and lineage specificity, based on data mostly in humans.

scholarly journals Role of Transposable Elements in Gene Regulation in the Human Genome

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 118
Author(s):  
Arsala Ali ◽  
Kyudong Han ◽  
Ping Liang
Keyword(s):  
Gene Regulation ◽  
Transposable Elements ◽  
Regulatory Sequences ◽  
Rna Sequences ◽  
Expression Of Genes ◽  
Wide Range ◽  
Lineage Specificity ◽  
Regulatory Rnas ◽  
Potential Factors ◽  
Interspersed Repeats

Transposable elements (TEs), also known as mobile elements (MEs), are interspersed repeats that constitute a major fraction of the genomes of higher organisms. As one of their important functional impacts on gene function and genome evolution, TEs participate in regulating the expression of genes nearby and even far away at transcriptional and post-transcriptional levels. There are two known principal ways by which TEs regulate the expression of genes. First, TEs provide cis-regulatory sequences in the genome with their intrinsic regulatory properties for their own expression, making them potential factors for regulating the expression of the host genes. TE-derived cis-regulatory sites are found in promoter and enhancer elements, providing binding sites for a wide range of trans-acting factors. Second, TEs encode for regulatory RNAs with their sequences showed to be present in a substantial fraction of miRNAs and long non-coding RNAs (lncRNAs), indicating the TE origin of these RNAs. Furthermore, TEs sequences were found to be critical for regulatory functions of these RNAs, including binding to the target mRNA. TEs thus provide crucial regulatory roles by being part of cis-regulatory and regulatory RNA sequences. Moreover, both TE-derived cis-regulatory sequences and TE-derived regulatory RNAs have been implicated in providing evolutionary novelty to gene regulation. These TE-derived regulatory mechanisms also tend to function in a tissue-specific fashion. In this review, we aim to comprehensively cover the studies regarding these two aspects of TE-mediated gene regulation, mainly focusing on the mechanisms, contribution of different types of TEs, differential roles among tissue types, and lineage-specificity, based on data mostly in humans.

scholarly journals Role of Transposable Elements in Gene Regulation in the Human Genome

2020 ◽  
Author(s):  
Arsala Ali ◽  
Kyudong Han ◽  
Ping Liang
Keyword(s):  
Gene Regulation ◽  
Transposable Elements ◽  
Human Genome ◽  
Regulatory Sequences ◽  
Rna Sequences ◽  
Expression Of Genes ◽  
Wide Range ◽  
Lineage Specificity ◽  
Regulatory Rnas ◽  
Potential Factors

Transposable elements (TEs), also known as mobile elements (MEs), are interspersed repeats that constitute a major fraction of the genomes of higher organisms. As one of their important functional impacts on gene function and genome evolution, TEs participate in regulating the expression of genes nearby and even far away at transcriptional and post-transcriptional levels. There are two principal ways by which TEs regulate expression of genes in the human genome. First, TEs provide cis-regulatory sequences in the genome. TEs’ intrinsic regulatory properties for their own expression make them potential factors for regulating the expression of the host genes. TE-derived cis-regulatory sites are found in promoter and enhancer elements, providing binding sites for a wide range of trans-acting factors. Second, TEs encode for regulatory RNAs. TEs sequences have been revealed to be present in a substantial fraction of miRNAs and long non-coding RNAs (lncRNAs), indicating their TE origin. Furthermore, TEs sequences were found to be critical for regulatory functions of these RNAs including binding to the target mRNA. TEs thus provide crucial regulatory roles by being part of cis-regulatory and regulatory RNA sequences. Moreover, both TE-derived cis-regulatory sequences and TE-derived regulatory RNAs, have been implicated to provide evolutionary novelty to gene regulation. These TE-derived regulatory mechanisms also tend to function in tissue-specific fashion. In this review, we aim to comprehensively cover the studies regarding these two aspects of TE-mediated gene regulation, mainly focusing on the mechanisms, contribution of different types of TEs, differential roles among tissue types, and lineage specificity, based on data mostly in humans.

scholarly journals Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes

2020 ◽  
Vol 375 (1795) ◽  
pp. 20190347 ◽  
Author(s):  
Vasavi Sundaram ◽  
Joanna Wysocka
Keyword(s):  
Gene Regulation ◽  
Transposable Elements ◽  
Regulatory Networks ◽  
Regulatory Elements ◽  
Regulatory Function ◽  
Specific Gene ◽  
Regulatory Sequences ◽  
Dependent Manner ◽  
Unique Contribution ◽  
Regulatory Potential

Eukaryotic gene regulation is mediated by cis -regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis -regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis -regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis -regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

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

2021 ◽  
Author(s):  
Nikolaos Lykoskoufis ◽  
Evarist Planet ◽  
Halit Ongen ◽  
Didier Trono ◽  
Emmanouil T Dermitzakis
Keyword(s):  
Colorectal Cancer ◽  
Transposable Elements ◽  
Genetic Effect ◽  
Regulatory Sequences ◽  
Driver Genes ◽  
Cancer Driver ◽  
Tumor Tissues ◽  
Interspersed Repeats ◽  
Methylation Patterns ◽  
The Impact

Abstract Transposable elements (TEs) are interspersed repeats that contribute to more than half of the human genome, and TE-embedded regulatory sequences are increasingly recognized as major components of the human regulome. Perturbations of this system can contribute to tumorigenesis, but the impact of TEs on gene expression in cancer cells remains to be fully assessed. Here, we analyzed 275 normal colon and 276 colorectal cancer (CRC) samples from the SYSCOL colorectal cancer cohort and discovered 10,111 and 5,152 TE expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively. Amongst the latter, 376 were exclusive to CRC, likely driven by changes in methylation patterns. We identified that transcription factors are more enriched in tumor-specific TE-eQTLs than shared TE-eQTLs, indicating that TEs are more specifically regulated in tumor than normal. Using Bayesian Networks to assess the causal relationship between eQTL variants, TEs and genes, we identified that 1,758 TEs are mediators of genetic effect, altering the expression of 1,626 nearby genes significantly more in tumor compared to normal, of which 51 are cancer driver genes. We show that tumor-specific TE-eQTLs trigger the driver capability of TEs subsequently impacting expression of nearby genes. Collectively, our results highlight a global profile of a new class of cancer drivers, thereby enhancing our understanding of tumorigenesis and providing potential new candidate mechanisms for therapeutic target development.

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

2021 ◽  
Author(s):  
Nikolaos M. R. Lykoskoufis ◽  
Evarist Planet ◽  
Halit Ongen ◽  
Didier Trono ◽  
Emmanouil T. Dermitzakis
Keyword(s):  
Colorectal Cancer ◽  
Transposable Elements ◽  
Genetic Effect ◽  
Regulatory Sequences ◽  
Driver Genes ◽  
Cancer Driver ◽  
Tumor Tissues ◽  
Interspersed Repeats ◽  
Methylation Patterns ◽  
The Impact

ABSTRACTTransposable elements (TEs) are interspersed repeats that contribute to more than half of the human genome, and TE-embedded regulatory sequences are increasingly recognized as major components of the human regulome. Perturbations of this system can contribute to tumorigenesis, but the impact of TEs on gene expression in cancer cells remains to be fully assessed. Here, we analyzed 275 normal colon and 276 colorectal cancer (CRC) samples from the SYSCOL colorectal cancer cohort and discovered 10,111 and 5,152 TE expression quantitative trait loci (eQTLs) in normal and tumor tissues, respectively. Amongst the latter, 376 were exclusive to CRC, likely driven by changes in methylation patterns. We identified that transcription factors are more enriched in tumor-specific TE-eQTLs than shared TE-eQTLs, indicating that TEs are more specifically regulated in tumor than normal. Using Bayesian Networks to assess the causal relationship between eQTL variants, TEs and genes, we identified that 1,758 TEs are mediators of genetic effect, altering the expression of 1,626 nearby genes significantly more in tumor compared to normal, of which 51 are cancer driver genes. We show that tumor-specific TE-eQTLs trigger the driver capability of TEs subsequently impacting expression of nearby genes. Collectively, our results highlight a global profile of a new class of cancer drivers, thereby enhancing our understanding of tumorigenesis and providing potential new candidate mechanisms for therapeutic target development.

scholarly journals Transposable elements generate regulatory novelty in a tissue-specific fashion

2018 ◽  
Author(s):  
Marco Trizzino ◽  
Aurélie Kapusta ◽  
Christopher D. Brown
Keyword(s):  
Gene Regulation ◽  
Transposable Elements ◽  
Active Regions ◽  
Long Terminal Repeat Retrotransposons ◽  
Regulatory Sequences ◽  
Evolutionary Novelty ◽  
Tissue Specific ◽  
Master Regulators ◽  
Long Interspersed Nuclear Elements ◽  
The Given

AbstractBackgroundTransposable elements (TE) are an important source of evolutionary novelty in gene regulation. However, the mechanisms by which TEs contribute to gene expression are largely uncharacterized.ResultsHere, we leverage Roadmap and GTEx data to investigate the association of TEs with active and repressed chromatin in 24 tissues. We find 112 human TE types enriched in active regions of the genome across tissues. SINEs and DNA transposons are the most frequently enriched classes, while LTRs are often enriched in a tissue-specific manner. We report across-tissue variability in TE enrichment in active regions. Genes with consistent expression across tissues are less likely to be associated with TE insertions. TE presence in repressed regions similarly follows tissue-specific patterns. Moreover, different TE classes correlate with different repressive marks: Long Terminal Repeat Retrotransposons (LTRs) and Long Interspersed Nuclear Elements (LINEs) are overrepresented in regions marked by H3K9me3, while the other TEs are more likely to overlap regions with H3K27me3. Young TEs are typically enriched in repressed regions and depleted in active regions. We detect multiple instances of TEs that are enriched in tissue-specific active regulatory regions. Such TEs contain binding sites for transcription factors that are master regulators for the given tissue. These TEs are enriched in intronic enhancers, and their tissue-specific enrichment correlates with tissue-specific variations in the expression of the nearest genes.ConclusionsWe provide an integrated overview of the contribution of TEs to human gene regulation. Expanding previous analyses, we demonstrate that TEs can potentially contribute to the turnover of regulatory sequences in a tissue-specific fashion.

scholarly journals Genome-wide analysis of the association of transposable elements with gene regulation suggests that Alu elements have the largest overall regulatory impact

2017 ◽  
Author(s):  
Lu Zeng ◽  
Stephen M. Pederson ◽  
Danfeng Cao ◽  
Zhipeng Qu ◽  
Zhiqiang Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Transposable Elements ◽  
Regulatory Sequences ◽  
Alu Elements ◽  
Genome Wide ◽  
A Genome ◽  
Regulatory Impact ◽  
Species Specific ◽  
Regulated Gene Expression

ABSTRACTNearly half of the human genome is made up of transposable elements (TEs) and there is evidence that TEs are involved in gene regulation. Here, we have integrated publicly available genomic, epigenetic and transcriptomic data to investigate this in a genome-wide manner. A bootstrapping statistical method was applied to minimize the confounder effects from different repeat types. Our results show that although most TE classes are primarily associated with reduced gene expression, Alu elements are associated with up regulated gene expression. Furthermore, Alu elements had the highest probability of any TE class of contributing to regulatory regions of any type defined by chromatin state. This suggests a general model where clade specific SINEs may contribute more to gene regulation than ancient/ancestral TEs. Finally, non-coding regions were found to have a high probability of TE content within regulatory sequences, most notably in repressors. Our exhaustive analysis has extended and updated our understanding of TEs in terms of their global impact on gene regulation, and suggests that the most recently derived types of TEs, i.e. clade or species specific SINES, have the greatest overall impact on gene regulation.

scholarly journals Identification of the conserved long non-coding RNAs in myogenesis

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anupam Bhattacharya ◽  
Simang Champramary ◽  
Tanya Tripathi ◽  
Debajit Thakur ◽  
Ilya Ioshikhes ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Muscle Development ◽  
Three Dimensional ◽  
C2c12 Cells ◽  
Mouse Muscle ◽  
Rna Molecules ◽  
Expression Of Genes ◽  
Novel Approach ◽  
Non Coding Rna ◽  
Topologically Associated Domains

Abstract Background Our understanding of genome regulation is ever-evolving with the continuous discovery of new modes of gene regulation, and transcriptomic studies of mammalian genomes have revealed the presence of a considerable population of non-coding RNA molecules among the transcripts expressed. One such non-coding RNA molecule is long non-coding RNA (lncRNA). However, the function of lncRNAs in gene regulation is not well understood; moreover, finding conserved lncRNA across species is a challenging task. Therefore, we propose a novel approach to identify conserved lncRNAs and functionally annotate these molecules. Results In this study, we exploited existing myogenic transcriptome data and identified conserved lncRNAs in mice and humans. We identified the lncRNAs expressing differentially between the early and later stages of muscle development. Differential expression of these lncRNAs was confirmed experimentally in cultured mouse muscle C2C12 cells. We utilized the three-dimensional architecture of the genome and identified topologically associated domains for these lncRNAs. Additionally, we correlated the expression of genes in domains for functional annotation of these trans-lncRNAs in myogenesis. Using this approach, we identified conserved lncRNAs in myogenesis and functionally annotated them. Conclusions With this novel approach, we identified the conserved lncRNAs in myogenesis in humans and mice and functionally annotated them. The method identified a large number of lncRNAs are involved in myogenesis. Further studies are required to investigate the reason for the conservation of the lncRNAs in human and mouse while their sequences are dissimilar. Our approach can be used to identify novel lncRNAs conserved in different species and functionally annotated them.

scholarly journals Fluorescent thermal shift-based method for detection of NF-κB binding to double-stranded DNA

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Peter D. Leitner ◽  
Ilja Vietor ◽  
Lukas A. Huber ◽  
Taras Valovka
Keyword(s):  
Dna Binding ◽  
Rational Design ◽  
Dissociation Constants ◽  
Inflammatory Diseases ◽  
Dimethyl Fumarate ◽  
Bioinformatic Analysis ◽  
Quantitative Detection ◽  
Regulatory Sequences ◽  
Wide Range ◽  
Inhibitory Drug

AbstractThe nuclear factor kappa B (NF-κB) family of dimeric transcription factors regulates a wide range of genes by binding to their specific DNA regulatory sequences. NF-κB is an important therapeutic target linked to a number of cancers as well as autoimmune and inflammatory diseases. Therefore, effective high-throughput methods for the detection of NF-κB DNA binding are essential for studying its transcriptional activity and for inhibitory drug screening. We describe here a novel fluorescence-based assay for quantitative detection of κB consensus double-stranded (ds) DNA binding by measuring the thermal stability of the NF-κB proteins. Specifically, DNA binding proficient NF-κB probes, consisting of the N-terminal p65/RelA (aa 1–306) and p50 (aa 1–367) regions, were designed using bioinformatic analysis of protein hydrophobicity, folding and sequence similarities. By measuring the SYPRO Orange fluorescence during thermal denaturation of the probes, we detected and quantified a shift in the melting temperatures (ΔTm) of p65/RelA and p50 produced by the dsDNA binding. The increase in Tm was proportional to the concentration of dsDNA with apparent dissociation constants (KD) of 2.228 × 10–6 M and 0.794 × 10–6 M, respectively. The use of withaferin A (WFA), dimethyl fumarate (DMF) and p-xyleneselenocyanate (p-XSC) verified the suitability of this assay for measuring dose-dependent antagonistic effects on DNA binding. In addition, the assay can be used to analyse the direct binding of inhibitors and their effects on structural stability of the protein probe. This may facilitate the identification and rational design of new drug candidates interfering with NF-κB functions.

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