The epigenetic landscape of Alu repeats delineates the structural and functional genomic architecture of colon cancer cells

Abstract

Cancer cells exhibit multiple epigenetic changes with prominent local DNA hypermethylation and widespread hypomethylation affecting large chromosomal domains. Epigenome studies often disregard the study of repeat elements owing to technical complexity and their undefined role in genome regulation. We have developed NSUMA (Next-generation Sequencing of UnMethylated Alu), a cost-effective approach allowing the unambiguous interrogation of DNA methylation in more than 130,000 individual Alu elements, the most abundant retrotransposon in the human genome. DNA methylation profiles of Alu repeats have been analyzed in colon cancers and normal tissues using NSUMA and whole-genome bisulfite sequencing. Normal cells show a low proportion of unmethylated Alu (1%-4%) that may increase up to 10-fold in cancer cells. In normal cells, unmethylated Alu elements tend to locate in the vicinity of functionally rich regions and display epigenetic features consistent with a direct impact on genome regulation. In cancer cells, Alu repeats are more resistant to hypomethylation than other retroelements. Genome segmentation based on high/low rates of Alu hypomethylation allows the identification of genomic compartments with differential genetic, epigenetic, and transcriptomic features. Alu hypomethylated regions show low transcriptional activity, late DNA replication, and its extent is associated with higher chromosomal instability. Our analysis demonstrates that Alu retroelements contribute to define the epigenetic landscape of normal and cancer cells and provides a unique resource on the epigenetic dynamics of a principal, but largely unexplored, component of the primate genome.

Genome-wide analysis of polymerase III–transcribed Alu elements suggests cell-type–specific enhancer function

“…Low DNA methylation has been associated with active transcription of Alu elements (Jordà et al 2017). Indeed, the levels of DNA methylation at expressed Alu elements in K562 or GM12878 cells were significantly lower than the levels at unexpressed Alu elements (Fig.…”

CGGBP1 regulates chromatin barrier activity and CTCF occupancy at repeats

“…Presence of CTCF-binding sites inside and in the vicinity of repeats makes this more plausible because binding of CGGBP1 to repetitive sequences flanking the CTCF target sites and motifs can constrain the binding of CTCF. A comparison of CTCF-binding sites and CGGBP1-binding sites in fact shows proximity as well as an overlap at L1 and Alu repeats (Estécio et al, 2012;Jordà et al, 2017;Kim, 2008) . CGGBP1 is also one of the marker proteins localizing to CTCF-bound enhancer-promoter loops.…”

Nutritional Factors Modulating Alu Methylation in an Italian Sample from The Mark-Age Study Including Offspring of Healthy Nonagenarians

“…Previous studies reported an age-dependent decline in genomic DNA methylation, both in global DNA and in Alu elements [13,14,17]. DNA Alu hypomethylation may promote an enhanced retrotransposon activity and genomic instability [12] and is associated with the severity of some age-related diseases [14][15][16][17]. In our study, we observed that Alu methylation at the CpG1 site do not display marked age-related changes, but lower levels of methylation at this site were found in elderly subjects over 65 years compared to the age class 55-64 years.…”

“…Alu hypomethylation has been found during aging [13] and it has been associated with the severity of age-related diseases such as diabetes [14], cancer [15], osteoporosis [16] and cardiovascular diseases [17]. Interestingly, hypomethylation and epigenetic age are delayed in centenarians' offspring [18,19], which are considered an optimal model to study biomarkers associated with human longevity.…”