Abstract
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.
Highlights
Mammalian-wide interspersed repeats (MIRs) are the most ancient family of transposable elements (TEs) in the human genome
MIRs are highly concentrated in enhancers As noted in the introduction, MIRs are the only TEs that show a positive association with tissue-specific gene expression [8]
We computed the fraction of MIRs in and around 20 kb loci centered on all genomic enhancers (n = 24,538 and 36,550 for K562 and HeLa cell-lines respectively) and compared it with MIR enrichment in the local genomic background
Summary
Mammalian-wide interspersed repeats (MIRs) are the most ancient family of transposable elements (TEs) in the human genome. MIRs 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. Human Alu short interspersed elements (SINEs) are predominantly found in GC- and gene-rich regions, whereas L1 long interspersed elements (LINEs) are most prevalent in low-GC and gene-poor. Alu elements are significantly associated with the breadth of gene expression across tissues [7,8]. Mammalian-wide interspersed repeats (MIRs) are the only TEs that show a positive association between their prevalence in-and-around genes and tissue-specific gene expression [8,12]
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