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Researchers ID Secondary DNA Structures Associated With Regulatory Regions of Cancer Genes

NEW YORK (GenomeWeb) – Building on a previous study in which researchers from the University of Cambridge developed a method to sequence secondary DNA structures known as G-quadruplexes, the same team applied it to ChIP-seq, identifying around 10,000 G4 structures in regulatory regions, promoters, and 5' untranslated regions of highly transcribed genes — especially in genes related to cancer.

"There have been a number of different connections made between these structures and cancer, but these have been largely hypothetical," Shankar Balasubramanian, senior author of the study published today in Nature Genetics, said in a statement. "But what we've found is that even in non-cancer cells, these structures seem to come and go in a way that's linked to genes being switched on or off."

In the study, the researchers applied the G4 ChIP-seq technique to a cell line known as HaCaT — a nononcogenic cell line derived from epidermal cells, but made immortal and with the ability to differentiate into any type of epidermal cell. G4 ChIP-seq identified 10,560 peaks.

Looking further into their findings, the researchers validated that the method was in fact identifying true G4 structures, and noted in the study that G4 formation was "predominantly restricted to regulatory, nucleosome-depleted regions in euchromatin."

In addition, the researchers found that the G4 structures were predominantly in regions where "transcription factors control cell fate and function," lead author of the study, Robert Hänsel-Hertsch, said in a statement. "The finding that these structures may help regulate the way that information is encoded and decoded in the genome will change the way we think this process works," he added.

Next, the researchers compared the HaCaT cell line to normal human skin cells. Looking at the G4 ChIP-seq sites that were present in the HaCaT cell line but not the normal skin cell line, the team found sites in cancer genes, including MYC, PTEN, and KRAS, "suggesting a link between increased proliferative capacity/immortalization and G4 structures."

The study authors wrote that they had previously demonstrated that the small molecule pyridostatin binds to G4 structures, and, indeed, when they compared the sensitivity of the HaCaT cells with the normal skin cells, they found the HaCaT cells were "seven times more sensitive to growth inhibition," a finding that "suggests a potential rationale for selective cancer intervention by G4 targeting," the authors wrote.

The G4 sites identified by the G4 ChiP-seq method showed "hallmarks of dynamic epigenetic features in chromatin primarily found in regulatory, nucleosome-depleted regions and correlate with genes showing elevated transcription," the authors wrote. In addition, the study illustrated the potential of G4 structures as a target in cancer treatment.