Prediction of Transposable Element Derived Enhancers Using Chromatin Modification Profiles

Huda, Ahsan; Tyagi, Eishita; Mariño-Ramírez, Leonardo; Bowen, Nathan J.; Jjingo, Daudi; Jordan, I. King

doi:10.1371/journal.pone.0027513

Cited by 24 publications

(25 citation statements)

References 38 publications

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“…We found that not only are MIRs highly concentrated in predicted enhancers, but they also constitute a significant part of the core of genic enhancers; this analysis identified many more putative MIR-derived enhancers than previously reported [22,33]. These MIR-derived enhancers have cell-type specific chromatin profiles that are highly similar to those seen for canonical enhancers.…”

Section: Introductionsupporting

confidence: 62%

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Mammalian-wide interspersed repeat (MIR)-derived enhancers and the regulation of human gene expression

et al. 2014

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BackgroundMammalian-wide interspersed repeats (MIRs) are the most ancient family of transposable elements (TEs) in the human genome. The deep conservation of MIRs initially suggested the possibility that they had been exapted to play functional roles for their host genomes. MIRs also happen to be the only TEs whose presence in-and-around human genes is positively correlated to tissue-specific gene expression. Similar associations of enhancer prevalence within genes and tissue-specific expression, along with MIRs’ previous implication as providing regulatory sequences, suggested a possible link between MIRs and enhancers.ResultsTo test the possibility that MIRs contribute functional enhancers to the human genome, we evaluated the relationship between MIRs and human tissue-specific enhancers in terms of genomic location, chromatin environment, regulatory function, and mechanistic attributes. This analysis revealed MIRs to be highly concentrated in enhancers of the K562 and HeLa human cell-types. Significantly more enhancers were found to be linked to MIRs than would be expected by chance, and putative MIR-derived enhancers are characterized by a chromatin environment highly similar to that of canonical enhancers. MIR-derived enhancers show strong associations with gene expression levels, tissue-specific gene expression and tissue-specific cellular functions, including a number of biological processes related to erythropoiesis. MIR-derived enhancers were found to be a rich source of transcription factor binding sites, underscoring one possible mechanistic route for the element sequences co-option as enhancers. There is also tentative evidence to suggest that MIR-enhancer function is related to the transcriptional activity of non-coding RNAs.ConclusionsTaken together, these data reveal enhancers to be an important cis-regulatory platform from which MIRs can exercise a regulatory function in the human genome and help to resolve a long-standing conundrum as to the reason for MIRs’ deep evolutionary conservation.

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Section: Introductionsupporting

confidence: 62%

“…And while MIRs are known to donate enhancers in a number of individual cases [21,22,33], these data show an even deeper relationship, namely that MIRs are substantially concentrated in enhancers genome-wide.…”

Section: Resultsmentioning

confidence: 99%

Mammalian-wide interspersed repeat (MIR)-derived enhancers and the regulation of human gene expression

et al. 2014

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“…The evolutionary process by which TE sequences are subverted for novel function by the host genome is known as "exaptation" (de Souza et al 2013). There is extensive literature demonstrating that TEs have contributed repeatedly and profoundly to the evolution of genome structure and function through the insertion of preformed sequence elements, both at the level of genomic DNA, e.g., transcription factor binding sites (Johnson et al 2006), splice sites (Sela et al 2010), enhancer elements (Huda et al 2011b), and promoters (Huda et al 2011a), and at the level of RNA, e.g., microRNA genes (Spengler et al 2014), recognition elements (Piriyapongsa and Jordan 2007), and protein-coding domains (Bowen and Jordan 2007).…”

Section: Te Sequences Are Abundantly Found In Lncrna Exonsmentioning

confidence: 99%

The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs

Johnson

Guigó

2014

RNA

283

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Our genome contains tens of thousands of long noncoding RNAs (lncRNAs), many of which are likely to have genetic regulatory functions. It has been proposed that lncRNA are organized into combinations of discrete functional domains, but the nature of these and their identification remain elusive. One class of sequence elements that is enriched in lncRNA is represented by transposable elements (TEs), repetitive mobile genetic sequences that have contributed widely to genome evolution through a process termed exaptation. Here, we link these two concepts by proposing that exonic TEs act as RNA domains that are essential for lncRNA function. We term such elements Repeat Insertion Domains of LncRNAs (RIDLs). A growing number of RIDLs have been experimentally defined, where TE-derived fragments of lncRNA act as RNA-, DNA-, and protein-binding domains. We propose that these reflect a more general phenomenon of exaptation during lncRNA evolution, where inserted TE sequences are repurposed as recognition sites for both protein and nucleic acids. We discuss a series of genomic screens that may be used in the future to systematically discover RIDLs. The RIDL hypothesis has the potential to explain how functional evolution can keep pace with the rapid gene evolution observed in lncRNA. More practically, TE maps may in the future be used to predict lncRNA function.

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“…First of all, a number of noncoding MIR sequences were found to be highly conserved, indicative of some functional, presumably regulatory, role (24). Later, it was shown that MIRs are enriched for open chromatin sites (25), encode regulatory RNAs (26), host gene promoters (27) and enhancers (28), and are also associated with tissue-specific expressed genes (29). Finally, and most importantly, MIRs are tRNA-derived SINEs (30) and their sequences include recognizable regulatory motifs, such as the promoter B-box element for Pol III binding, which are thought to be important for insulator activity.…”

Section: Significancementioning

confidence: 99%

MIR retrotransposon sequences provide insulators to the human genome

Wang

Vicente-García

Seruggia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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108

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Insulators are regulatory elements that help to organize eukaryotic chromatin via enhancer-blocking and chromatin barrier activity. Although there are several examples of transposable element (TE)-derived insulators, the contribution of TEs to human insulators has not been systematically explored. Mammalian-wide interspersed repeats (MIRs) are a conserved family of TEs that have substantial regulatory capacity and share sequence characteristics with tRNA-related insulators. We sought to evaluate whether MIRs can serve as insulators in the human genome. We applied a bioinformatic screen using genome sequence and functional genomic data from CD4 + T cells to identify a set of 1,178 predicted MIR insulators genome-wide. These predicted MIR insulators were computationally tested to serve as chromatin barriers and regulators of gene expression in CD4 + T cells. The activity of predicted MIR insulators was experimentally validated using in vitro and in vivo enhancer-blocking assays. MIR insulators are enriched around genes of the T-cell receptor pathway and reside at T-cell-specific boundaries of repressive and active chromatin. A total of 58% of the MIR insulators predicted here show evidence of T-cell-specific chromatin barrier and gene regulatory activity. MIR insulators appear to be CCCTC-binding factor (CTCF) independent and show a distinct local chromatin environment with marked peaks for RNA Pol III and a number of histone modifications, suggesting that MIR insulators recruit transcriptional complexes and chromatin modifying enzymes in situ to help establish chromatin and regulatory domains in the human genome. The provisioning of insulators by MIRs across the human genome suggests a specific mechanism by which TE sequences can be used to modulate gene regulatory networks.

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Prediction of Transposable Element Derived Enhancers Using Chromatin Modification Profiles

Cited by 24 publications

References 38 publications

Mammalian-wide interspersed repeat (MIR)-derived enhancers and the regulation of human gene expression

Mammalian-wide interspersed repeat (MIR)-derived enhancers and the regulation of human gene expression

The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs

MIR retrotransposon sequences provide insulators to the human genome

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