Massive contribution of transposable elements to mammalian regulatory sequences

Rayan, Nirmala Arul; Rosario, Ricardo C.H. del; Prabhakar, Shyam

doi:10.1016/j.semcdb.2016.05.004

Cited by 20 publications

(13 citation statements)

References 59 publications

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“…Nearly half of the human genome is composed of transposable elements (TEs), which are increasingly being recognized not just as parasitic DNA, but as an important source of regulatory innovation for the host ( Chuong et al, 2017 ; Feschotte, 2008 ; Rayan et al, 2016 ; Thompson et al, 2016 ). In particular, endogenous retroviruses (ERVs), which comprise about 8% of the human genome, are sequences derived from ancient retroviruses whose germ-line infections have persisted through millions of years of evolution ( Feschotte and Gilbert, 2012 ; Johnson, 2015 ; International Human Genome Sequencing Consortium et al, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

“…Epigenomic mapping studies detected cell type-selective active enhancer signatures at thousands of LTRs, suggesting that acquisition of tissue-specific or inducible regulatory functions by these elements is a widespread phenomenon that may have profound effects on host gene regulatory networks ( Bourque et al, 2008 ; Chuong et al, 2013 ; Huda et al, 2010 ; Kunarso et al, 2010 ; Martens et al, 2005 ; Sundaram et al, 2014 ; Thurman et al, 2012 ; Trizzino et al, 2017 ; Jiang et al, 2014 ; Wang et al, 2012 ). Furthermore, emerging evidence suggests that a large proportion of primate-specific enhancer/promoter sequences, as well as those that changed their activity most recently, since the separation of humans from chimpanzees, originate from TEs ( Jacques et al, 2013 ; Prescott et al, 2015 ; Rayan et al, 2016 ; Trizzino et al, 2017 ). Thus, understanding the functional impact of TEs on gene regulation is essential for comprehending the emergence of primate- and human-specific traits.…”

Section: Introductionmentioning

confidence: 99%

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Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation

Fuentes

Swigut

Wysocka

2018

eLife

166

184

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Recent work suggests extensive adaptation of transposable elements (TEs) for host gene regulation. However, high numbers of integrations typical of TEs, coupled with sequence divergence within families, have made systematic interrogation of the regulatory contributions of TEs challenging. Here, we employ CARGO, our recent method for CRISPR gRNA multiplexing, to facilitate targeting of LTR5HS, an ape-specific class of HERVK (HML-2) LTRs that is active during early development and present in ~700 copies throughout the human genome. We combine CARGO with CRISPR activation or interference to, respectively, induce or silence LTR5HS en masse, and demonstrate that this system robustly targets the vast majority of LTR5HS insertions. Remarkably, activation/silencing of LTR5HS is associated with reciprocal up- and down-regulation of hundreds of human genes. These effects require the presence of retroviral sequences, but occur over long genomic distances, consistent with a pervasive function of LTR5HS elements as early embryonic enhancers in apes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation

Fuentes

Swigut

Wysocka

2018

eLife

166

184

View full text Add to dashboard Cite

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“…Multiple elegant studies have demonstrated that TE sequences play a functional role in eukaryotic gene regulation [ 10 – 32 ]. Consistently, we recently demonstrated that TEs are the primary source of evolutionary novelty in primate gene regulation, and reported that the large majority of newly evolved human and ape specific liver cis-regulatory elements are derived from TE insertions [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Transposable elements generate regulatory novelty in a tissue-specific fashion

2018

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BackgroundTransposable 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 families enriched in active regions of the genome across tissues. Short Interspersed Nuclear Elements (SINEs) and DNA transposons are the most frequently enriched classes, while Long Terminal Repeat Retrotransposons (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: 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.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4850-3) contains supplementary material, which is available to authorized users.

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“…Although previous studies have suggested a role for transposable elements (TEs) in the evolution of gene regulation, validating the functional contribution of TEs in mammalian gene regulation remains a challenge (McClintock 1950(McClintock , 1984Britten and Davidson 1969;Davidson and Britten 1979;Jordan et al 2003;Bejerano et al 2006;Wang et al 2007;Bourque et al 2008;Sasaki et al 2008;Markljung et al 2009;Kunarso et al 2010;Lynch et al 2011Lynch et al , 2015Schmidt et al 2012;Chuong et al 2013Chuong et al , 2016Jacques et al 2013;Xie et al 2013;del Rosario et al 2014;Sundaram et al 2014;Du et al 2016;Rayan et al 2016;Ward et al 2017).…”

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confidence: 99%

Transposable elements are the primary source of novelty in primate gene regulation

et al. 2017

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Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNAseq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP-seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species. Conserved CRE function is associated with sequence conservation, proximity to coding genes, cell-type specificity, and transcription factor binding. Newly evolved CREs are enriched in immune response and neurodevelopmental functions. We further demonstrate that conserved CREs bind master regulators, suggesting that while CREs contribute to species adaptation to the environment, core functions remain intact. Newly evolved CREs are enriched in young transposable elements (TEs), including Long-Terminal-Repeats (LTRs) and SINE-VNTR-Alus (SVAs), that significantly affect gene expression. Conversely, only 16% of conserved CREs overlap TEs. We tested the cis-regulatory activity of 69 TE subfamilies by luciferase reporter assays, spanning all major TE classes, and showed that 95.6% of tested TEs can function as either transcriptional activators or repressors. In conclusion, we demonstrated the critical role of TEs in primate gene regulation and illustrated potential mechanisms underlying evolutionary divergence among the primate species through the noncoding genome.

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Massive contribution of transposable elements to mammalian regulatory sequences

Cited by 20 publications

References 59 publications

Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation

Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation

Transposable elements generate regulatory novelty in a tissue-specific fashion

Transposable elements are the primary source of novelty in primate gene regulation

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