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French Team Develops Array to Profile Methylation in Repetitive DNA Elements

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A team of French researchers has developed an array for profiling DNA methylation in human repetitive DNA elements and has used the technology to determine the relationship between such methylation and the development and progression of cancer.

Research team member Beatrice Horard told BioArray News this week that she and colleague Eric Gilson developed the array, called RepArray, while they both worked in the Laboratory of the Molecular Biology of the Cell at Université Lyon. Gilson now heads a lab at Université Nice.

According to Horard, she and Gilson were "convinced" that the mass of repetitive sequences present in the eukaryote genome was more than only "junk" DNA and decided to design an approach to evaluate the epigenetic status of the repetitive content of the human genome.

When they initiated the project in 2005, arrays were not available to interrogate reptitive DNA elements, Horard said. There were two reasons for this: the idea that repetitive DNA was junk DNA, and technical issues that limited the interpretation of such DNA elements.

Horard, Gilson, and colleagues designed RepArray by selecting sequences they deemed representative of a "whole family or of a subset of elements inside a given family" of sequences. The final chip, which the researchers described in a recently published Methods in Molecular Biology paper, consists of 236 prototypic oligonucleotides that span the four main categories of human repeats: tandem satellites found in centromeric, pericentromeric, and subtelomeric heterochromatin; interspersed transposable elements, such as LTR- and non-LTR retrotransposons as well as DNA transposons, according to the paper.

The Ecole Normale Supérieure's Biology Department Genomic Service printed the arrays at its facility in Paris.

"The main advantage of our array is that it gives a global picture ... of what is going on for a repeat family and ... for several different [such] families at the same time," Horard said.

The team combined RepArray with a methylated DNA immunoprecipitation approach, called MeDIP, to delineate DNA methylation changes after chemical or genetic disruption of DNA methyltransferase activity in cells, according to the paper. The authors suggest that MeDIP-on-RepArray "might serve as a workflow guideline for screening DNA methylation changes on repetitive elements during development and aging, among tissues, and in various types of stress or pathological situations."

After developing RepArray, the team validated the chip for methylation analysis of well-characterized cancer cell lines — HCT 116 and HCT116 DnmtKO — and also for the transcriptional study of repeats using the thermal stress model. Following this first validation step, they used the array to screen the repetitive sequences, allowing them to "pinpoint particular transcriptional variations under various conditons," such as telomeric dysfunction, Horard said.

Even though seven years have elapsed since the researchers first designed the array, Horard said that there are still no commercial arrays available that focus on repetitive sequences. "Some arrays cover partially the repetitive compartment but none can give a global picture of what is going on a whole family," she said.

As such, the authors claim that MeDIP-on-RepArray is a "relatively low-cost, well-suited approach" for screening DNA methylation changes that occur during development and aging, as well as methylation differences between diseased and healthy tissues or between genetically modified and unmodified control cells.

Still, Horard acknowleged that the tool might soon be obsolete. "In my opinion, the best way today to look at the repetitive compartment is a sequencing approach [such as] ChIP-seq or RNA-seq," she said. "Maybe the RepArray approach is still cost effective compared to the sequencing based approaches," Horard added, "but will this be true in two or three years?"

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