Transposable elements contribute to cell and species-specific chromatin looping and gene regulation in mammalian genomes

Diehl, Adam; Ouyang, Ningxin; Boyle, Alan P.

doi:10.1038/s41467-020-15520-5

Cited by 98 publications

(87 citation statements)

References 78 publications

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“…However, whether the CTCF bound to cVM-IAPs contributes to interactions with specific loci is yet to be determined. It has been shown in both mouse and human that TE insertions enriched for CTCF induce differential loop formation that is significantly associated with effects on gene expression (Diehl et al 2020). Our results indicate that epigenetic differences at TEs might also influence CTCF-mediated conformational states.…”

Section: Discussionmentioning

confidence: 56%

“…CTCF is important for establishing chromatin architecture (Filippova et al 1996;Moon et al 2005;Phillips and Corces 2009;Van Bortle et al 2014) and recent findings suggest that TEs bound by CTCF can contribute to chromatin looping, which in turn can influence gene regulation (Zhang et al 2019;Choudhary et al 2020;Diehl et al 2020). Therefore, we hypothesized that inter-individual variation in CTCF binding at cVM-IAPs could contribute to variation in genome topology.…”

Section: Chromatin Interactions With Cvm-iapsmentioning

confidence: 98%

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Genomic properties of variably methylated retrotransposons in mouse

Elmer

Hay

Kessler

et al. 2020

Preprint

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Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit inter-individual variability in this methylation (VM-IAPs) with implications for genome function. Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis. Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation.

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Section: Discussionmentioning

confidence: 56%

Section: Chromatin Interactions With Cvm-iapsmentioning

confidence: 98%

Genomic properties of variably methylated retrotransposons in mouse

Elmer

Hay

Kessler

et al. 2020

Preprint

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“…Many of these pMEIs are far from the associated genes. These pMEIs may impact gene regulation through several mechanisms, such as serving as distal enhancers [45,46] or altering chromatin looping structure [21,37]. An interesting observation is that the effects of pMEIs on expression and splicing were highly correlated for some genes (Fig.…”

Section: Discussionmentioning

confidence: 97%

“…Many diseases, including cancer [ 10 ] and psychiatric disorders [ 11 ], are associated with the activities of MEs [ 12 , 13 ]. In addition to causing genomic structural changes, MEs can also alter mRNA splicing [ 14 ] and gene expression levels [ 15 , 16 ] via a wide variety of mechanisms, including acting as promoters [ 17 ], enhancers [ 18 ], splicing sites [ 19 ], and terminators for transcription [ 20 ] and affecting chromatin looping [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Polymorphic mobile element insertions contribute to gene expression and alternative splicing in human tissues

et al. 2020

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Background: Mobile elements are a major source of structural variants in the human genome, and some mobile elements can regulate gene expression and transcript splicing. However, the impact of polymorphic mobile element insertions (pMEIs) on gene expression and splicing in diverse human tissues has not been thoroughly studied. The multi-tissue gene expression and whole genome sequencing data generated by the Genotype-Tissue Expression (GTEx) project provide a great opportunity to systematically evaluate the role of pMEIs in regulating gene expression in human tissues. Results: Using the GTEx whole genome sequencing data, we identify 20,545 highquality pMEIs from 639 individuals. Coupling pMEI genotypes with gene expression profiles, we identify pMEI-associated expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) in 48 tissues. Using joint analyses of pMEIs and other genomic variants, pMEIs are predicted to be the potential causal variant for 3522 eQTLs and 3717 sQTLs. The pMEI-associated eQTLs and sQTLs show a high level of tissue specificity, and these pMEIs are enriched in the proximity of affected genes and in regulatory elements. Using reporter assays, we confirm that several pMEIs associated with eQTLs and sQTLs can alter gene expression levels and isoform proportions, respectively. Conclusion: Overall, our study shows that pMEIs are associated with thousands of gene expression and splicing variations, indicating that pMEIs could have a significant role in regulating tissue-specific gene expression and transcript splicing. Detailed mechanisms for the role of pMEIs in gene regulation in different tissues will be an important direction for future studies.

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“…S 1 E). Human CTCF data were originally analyzed as part of a study on the effects of transposable element (TE) activity on CTCF binding site content in mammalian genomes [ 15 ]. In keeping with this, dog, horse, and elephant were chosen as outgroups to yield phylogenetic tree that encompasses two major groups of mammals: Atlantogenata and Boreoeutheria, spanning the primary activity periods for several TE types associated with CTCF binding (Fig.…”

Section: Methodsmentioning

confidence: 99%

MapGL: inferring evolutionary gain and loss of short genomic sequence features by phylogenetic maximum parsimony

Diehl

Boyle

2020

BMC Bioinformatics

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Background Comparative genomics studies are growing in number partly because of their unique ability to provide insight into shared and divergent biology between species. Of particular interest is the use of phylogenetic methods to infer the evolutionary history of cis-regulatory sequence features, which contribute strongly to phenotypic divergence and are frequently gained and lost in eutherian genomes. Understanding the mechanisms by which cis-regulatory element turnover generate emergent phenotypes is crucial to our understanding of adaptive evolution. Ancestral reconstruction methods can place species-specific cis-regulatory features in their evolutionary context, thus increasing our understanding of the process of regulatory sequence turnover. However, applying these methods to gain and loss of cis-regulatory features historically required complex workflows, preventing widespread adoption by the broad scientific community. Results MapGL simplifies phylogenetic inference of the evolutionary history of short genomic sequence features by combining the necessary steps into a single piece of software with a simple set of inputs and outputs. We show that MapGL can reliably disambiguate the mechanisms underlying differential regulatory sequence content across a broad range of phylogenetic topologies and evolutionary distances. Thus, MapGL provides the necessary context to evaluate how genomic sequence gain and loss contribute to species-specific divergence. Conclusions MapGL makes phylogenetic inference of species-specific sequence gain and loss easy for both expert and non-expert users, making it a powerful tool for gaining novel insights into genome evolution.

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Transposable elements contribute to cell and species-specific chromatin looping and gene regulation in mammalian genomes

Cited by 98 publications

References 78 publications

Genomic properties of variably methylated retrotransposons in mouse

Genomic properties of variably methylated retrotransposons in mouse

Polymorphic mobile element insertions contribute to gene expression and alternative splicing in human tissues

MapGL: inferring evolutionary gain and loss of short genomic sequence features by phylogenetic maximum parsimony

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