How To Silence Your Neighbor – Tips From A Transposon
Did you know that nearly half of our DNA consists of transposable elements? Until recently, this was believed to be a product of transposon duplication and random insertion into the genome. Estécio et al. recently proposed a new model suggesting that the distribution of transposable elements may not be random, but instead driven by evolution, and they suggest a function for specific SINE DNA repeat elements as epigenetic silencing centers.
In support of their model, the authors demonstrated that SINE B1 elements reduced transcription of a luciferase reporter when present on the same plasmid. The SINE B1 elements appeared to repress gene expression from the plasmids epigenetically, but the mechanism differed for the different promoters as one promoter (Cdkn2d) showed a persistent increase in DNA methylation while another promoter (p14Arf) exhibited an initial increase in DNA methylation that was later replaced by histone-based epigenetic silencing. A third promoter (Mlh1), however, was resistant to SINE-mediated epigenetic silencing, indicating that promoter context is important. The SINE B1 elements themselves remained free of DNA methylation, but were associated with histones containing repressive marks (H3K9me2 and H3K27me3). Removal of repetitive DNA elements also resulted in increased promoter activity in several human cell lines. Finally, the authors performed a computational analysis determining the abundance of SINE repeats +/- 10 kB from the transcriptional start site (TSS) of promoters bound by insulator proteins such as CTCF, USF1, and USF2 relative to those not bound by insulating proteins. These insulator proteins have previously been shown to act as barriers to the spread of heterochromatin. As the authors expected, genes bound by insulators were more tolerant of SINE elements adjacent to the TSS in non-CpG island promoters.
Taken together, these results provide evidence that both human and mouse SINE elements can facilitate epigenetic changes to nearby promoters via DNA methylation and chromatin modifications, resulting in transcriptional silencing. As a result, SINE elements are less common near the TSS of annotated genes, but more permissible when the region is protected from heterochromatinization by insulating proteins. More research is necessary to determine the epigenetic effect of different classes of retrotransposons on the genomic regions surrounding insertion, but it seems that repetitive DNA elements contribute to the higher order organization of mammalian genomes. What do you think? Is the continuing evolution of the human genome being driven by repetitive DNA elements?
Estécio MR, Gallegos J, Dekmezian M, Lu Y, Liang S, Issa JP. (2012) SINE Retrotransposons Cause Epigenetic Reprogramming of Adjacent Gene Promoters. Mol Cancer Res. 10(10):1332-42.
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