SINE Retrotransposons Cause Epigenetic Reprogramming of Adjacent Gene Promoters

Abstract

Almost half of the human genome and as much as 40% of the mouse genome is composed of repetitive DNA sequences. The majority of these repeats are retrotransposons of the SINE and LINE families, and such repeats are generally repressed by epigenetic mechanisms. It has been proposed that these elements can act as methylation centers from which DNA methylation spreads into gene promoters in cancer. Contradictory to a methylation center function, we have found that retrotransposons are enriched near promoter CpG islands that stay methylation-free in cancer. Clearly, it is important to determine which influence, if any, these repetitive elements have on nearby gene promoters. Using an in vitro system, we confirm here that SINE B1 elements can influence the activity of downstream gene promoters, with acquisition of DNA methylation and loss of activating histone marks, thus resulting in a repressed state. SINE sequences themselves did not immediately acquire DNA methylation, but were marked by H3K9me2 and H3K27me3. Moreover, our bisulfite sequencing data did not support that gain of DNA methylation in gene promoters occurred by methylation spreading from SINE B1 repeats. Genome-wide analysis of SINE repeats distribution showed that their enrichment is directly correlated with the presence of USF1, USF2 and CTCF binding, proteins with insulator function. In summary, our work supports the concept that SINE repeats interfere negatively with gene expression and that their presence near gene promoters is counter-selected, except when the promoter is protected by an insulator element.

Aging and epigenetic drift: a vicious cycle

“…This hypothesis does not account for some of the peculiarities of the process, such as genomic specificity. Studies have shown that the affected genes can be predicted to some extent using genomic features such as nearby retrotransposon density (48) (a high density is associated with fewer changes with age), occupancy by polycomb group pro teins in embryonic cells (33) (with polycomb group targets showing more agerelated changes), direct association with specific genomic sequences (49), and inverse association with CTCF binding sites (50). Additionally, baseline gene expression is also likely to influ ence this process (51).…”

Domesticated transposable element gene products in human cancer

“…16,17 Aside from direct disruption via insertion within genes, mobilized TEs can exert position effects on loci near the site of integration by disrupting normal mechanisms of regulated expression. 18 In some cases, TE-initiated transcription can proceed through neighboring loci, leading to the generation of chimeric transcripts that may actively promote neoplastic transformation.…”

Consequences of ongoing retrotransposition in mammalian genomes

“…86 Inclusion of mouse SINE B1 elements or Alu sequences upstream of reporter gene promoters led to increased gene repression and epigenetic modifications with time, though the SINE copies were unmethylated. 87 A particular mouse SINE B2 element and a subfamily of mouse SINE B1 were found to function as boundary elements that influenced dynamic changes in chromatin and transcriptional regulation, which required simultaneous RNA polymerase III sense transcription and RNA polymerase II antisense transcription of the SINE or the transition from RNA polymerase III transcription to RNA polymerase II transcription of the same DNA strand of the SINE, respectively. 88,89 Recent high throughput sequencing of human and mouse transcription start sites (TSSs) identified that retrotransposon TSSs comprised a surprisingly large percentage of total TSSs, ∼3%-8% and ∼2%-4%, in different tissues from humans and mice, respectively.…”