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

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.

Whole-genome expression analysis of mammalian-wide interspersed repeat elements in human cell lines

“…A recent study, showing that MIR elements are highly enriched in the enhancer state of chromatin in K562 and HeLa cell lines 9 prompted us to investigate whether our intergenic/antisense expression-positive MIRs found in the same cell lines were among those found by this study. We intersected the coordinates of our expression-positive MIRs with those of the MIR elements found to be enriched in enhancers (lifted over from NCBI36/hg18 to GRCh37/hg19), but we found only one overlapping MIR among the fully intronic sense-oriented dataset.…”

“…When K562 cells were considered, a higher percentage (36%, 15 MIRs) of intergenic/antisense expression-positive MIRs where found bound by one or more Pol III components, while the percentage drop down to 3% (4 MIRs) when considering the 119 MIRs fully contained within introns of Pol II genes in sense orientation (data not shown). In K562 cells we found significant enrichment for BDP1, TFIIIC110 and RPC155 ( P values 5.2 × 10  −   9 , 9.7 × 10  −   6 and <2.2 × 10  −   16 , respectively) in intergenic/antisense expression-positive MIRs. It is interesting to compare these results with those previously reported for Alus 17 .…”

“…In the human genome, there are more than 500,000 annotated MIRs 9 . Based on their sequence similarity, they have been grouped into 4 subfamilies named MIR, MIRb, MIRc, and MIR3.…”

“…Nevertheless, it can be speculated that since part of these elements are still transcriptionally active at least in the human and mouse genome, 11 changes in the 3′ tail due to sequence mutations could potentially rescue the retrotransposition potential of some of them. Recent studies have shown that enhancers are a platform from which MIRs can exert a regulatory function in the human genome 9 and that MIRs can also serve as insulators acting as chromatin barriers or enhancer-blocking elements 15 . Nothing is known, however, about the possible involvement of MIR expression in their role at enhancers/insulators.…”

Characterization and distribution of repetitive elements in association with genes in the human genome

“…In this study, we focused on the repeat elements that are located near an annotated gene, and aimed to exploit the regulatory functions of these elements. Though both types of repetitive elements have been suggested to be involved in the regulation of gene expression at various levels (Jjingo et al, 2014), the underlying mechanisms of regulatory action are different. The low complexity DNA and tandem repeats mediate gene expression through the interaction with specific DNA-or RNA-binding proteins (Chen et al, 2007;Chatterjee and Pal, 2009); therefore, these repeats exert specific effect to control the expression of the neighboring genes (i.e, a cis-effect).…”