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Genome information is encoded in three dimensions, and we are only just beginning to decipher this 3D structure
Research has shown that DNA is more likely to break in regions where its 3D structure is most fragile. Cancer-associated mutations also occur more in these areas
The international CNIO-CaixaResearch Frontiers Meeting analysed the role of the genome structure in a number of areas, from the neurotoxicity of chemotherapy to drug addiction and obesity
If the human genome is ‘the book of life’, its pages are folded into a complex origami figure. Moreover, in this book the meanings of sentences change according to the physical closeness between the words, once the paper is folded. In other words, genome information is encoded in three dimensions, and we are only now beginning to decipher this 3D structure.
The discovery that the 3D form of the genome influences genetic information – which genes are expressed at which point, for example – is one of the main paradigm shifts that has occurred in biology in recent decades. It can be seen as a nod from nature to the human effort to understand it: to understand the information in the genome, it is not enough to sequence it, we must discover how DNA folds in the nucleus of cells.
Twenty international leaders in this area gathered together at the CNIO-CaixaResearch Frontiers Meeting on ‘Genome Organisation and Stability’, held recently at CNIO (National Cancer Research Centre) to analyse the current state of knowledge.
Two metres within 10 thousandths of a millimetre
When fully unravelled, the DNA of a human cell measures two metres; it fits within the nucleus of cells – ten microns in diameter – because it folds. When folded, very separate sections of genetic material are brought into contact with each other in the DNA chain, and it is that contact which activates and deactivates genes. Errors in the genome’s 3D structure are related to diseases, including cancer.
“DNA folding determines how the cell reads, interprets, and maintains information in the genome; its study is attracting a great deal of attention. We are just beginning to understand the connections between the three-dimensional organisation of the genome and key processes in the emergence and progression of cancer, such as the repair of DNA damage,” say CNIO researchers Felipe Cortés, Ana Losada and Oscar Fernández-Capetillo, organisers of this congress together with Andre Nussenzweig, from the US National Cancer Institute.
From neurotoxicity to addiction and obesity
The organisation of the genome affects all bodily processes, so the congress touched on various topics: “There has been talk about why chemotherapy can damage our brain, or how obesity is passed down through the generations. These problems, although it might seem incredible, all begin with how the genome is compacted and how the cell manages to work with this information,” says Fernández Capetillo.
We have progressively been discovering the importance of the genome’s 3-D structure. The new techniques developed in recent decades have revealed that distant parts of the DNA chain are actually interacting.
This has allowed researchers to generate “maps of how the genome is organised, which have been crossed with maps of where the genome breaks,” explains Cortés. “We have seen that DNA is more likely to break in regions where it is structurally most fragile. And if you look at cancer-associated mutations, they also coincide with these areas.”
Organisation of the genome and fragility of chromosomes
One of the pioneers in this area is André Nussenzweig, with a paper entitled ‘Genome Organization Drives Chromosome Fragility”. This finding put Nussenzweig on the trail of a new area of research, which links breaks in the genome to neuron activity and the toxicity of chemotherapy in the brain.
Ana Pombo, from the Max Delbrück Center in Berlin, has created a key technique that reveals the 3D structure of the genome: GAM, Genome Architecture Mapping. Pombo developed this technique in 2017 and now applies it to the research of conditions such as autism and epilepsy, and the effect of drug addiction on neurons.
Ana Losada, head of the Chromosome Dynamics Group at CNIO, presented her work on cohesin, the protein that enables the genome to fold by forming DNA loops. Those loops are “what allows our DNA to fit in a tiny container like the nucleus of cells,” she explains.
Cohesin binds to DNA in a precise place and moves in a way that generates longer and longer loops, until it is released or until an obstacle stops and temporarily stabilises it . “These loops organise genetic material within the nucleus and facilitate communication between distant regions in the chromosome, for example genes and their regulatory elements,” Losada adds.