Researchers uncover how 3D genome rewiring drives breast cancer progression
A new international study led by Professor David Tremethick at the John Curtin School of Medical Research (JCSMR), Australian National University and Professor Jonas Paulsen from the University of Oslo, has revealed how the three-dimensional (3D) structure of the human genome is dramatically reorganised during breast cancer progression.
Published in Genome Research, the study provides a detailed look at how the physical folding of DNA inside the nucleus changes as healthy breast cells evolve into malignant cancer cells.
Professor David Tremethick said, “Our genome isn’t just a linear sequence — it’s folded in 3D space, and we have shown as normal breast cells turn cancerous, this 3D folding becomes disordered, changing which genes interact and, ultimately, which genes are activated or silenced.”
Professor Jonas Paulsen said “One of the study’s most striking and unexpected findings was the discovery of a previously unrecognised genomic rearrangement: a segment of DNA containing the MYC oncogene (normally on Chromosome 8) was found inserted into an active subcompartment of Chromosome 10.” This event created new enhancer contacts, molecular switches that turned up MYC’s activity, fuelling cancer-related gene expression.
Professor David Tremethick said, “It’s like the road system of a city being rearranged, roads that once connected quiet suburbs now link to busy downtown districts — changing the entire flow of information.”
“Targeting the genome’s 3D organisation is an emerging frontier,” Professor Paulsen noted. “As we learn more about how spatial structure drives cancer, we may be able to design interventions that reset these aberrant configurations.”
Key experimental work, including Hi-C and RNA sequencing library construction and Illumina sequencing, was performed at the Biomolecular Resource Facility within the JCSMR by Dr Maxim Nekrasov. He said that these technologies were critical to detecting the fine-scale changes in chromatin interactions associated with the malignant processes.