Cancer does not merely rewrite the genetic letters of the genome; it can also reorganize the vast three-dimensional structure in which those letters are stored. A new review by Franceschini, Georgakopoulou, Ciriello and colleagues examines how oncogenic changes reshape the spatial architecture of chromatin, and how those architectural changes can, in turn, help cancer cells acquire and maintain malignant properties. The central message is that the genome’s physical configuration is not passive packaging. It is an active layer of biological information that can influence which genes are switched on, which remain silent and how cells respond to genetic damage.
Inside a healthy human cell, nearly two metres of DNA must be compacted into a microscopic nucleus. This is achieved by wrapping DNA around histone proteins to form chromatin, which is then folded through several levels of organization. Chromatin is arranged into chromosomes occupying distinct nuclear territories, while regions with similar activity are grouped into compartments. Within these compartments, topologically associating domains, or TADs, bring neighbouring regulatory elements into preferred physical neighbourhoods. Even more precise contacts, known as chromatin loops, can connect gene promoters with distant enhancers that control their activity. Together, these structures help determine how the genome operates in space and time.
The review describes cancer-associated remodelling at each of these scales. Changes in chromosome structure can alter how entire genomic regions are positioned within the nucleus. Shifts between active and inactive chromatin compartments can modify the overall transcriptional state of large DNA segments. Disruption of domain boundaries may allow enhancers to communicate with genes that they would normally be unable to reach, while new or rearranged loops can establish abnormal regulatory connections. These events may activate oncogenes, silence tumour-suppressor genes or change the way cancer cells respond to signals from their environment.
One important source of three-dimensional disruption is genetic mutation. Structural variants such as deletions, duplications, inversions and translocations can physically rearrange the DNA sequences that form regulatory landscapes. A mutation does not need to occur inside a gene to have a powerful effect. If it removes a boundary separating an enhancer from an unrelated gene, for example, the enhancer may become available to the wrong promoter. Similarly, a rearrangement can place a powerful regulatory element next to an oncogene, creating persistent gene activation. In this way, the biological consequence of a genetic alteration may depend not only on the sequence that is changed, but also on the spatial relationships that are created or destroyed.
Cancer cells also reshape chromatin through epigenetic mechanisms, which alter gene activity without changing the underlying DNA sequence. Chemical modifications of histones, DNA methylation and the action of chromatin-remodelling complexes can change how tightly DNA is packaged and which regulatory regions are accessible to transcription factors. These changes can weaken normal boundaries, reorganize contacts between enhancers and promoters, or convert silent chromatin into an active state. Because epigenetic marks are often reversible, they may provide cancer cells with a degree of flexibility, allowing different cell populations within the same tumour to adopt distinct regulatory programmes.
The relationship between genome alterations and chromatin architecture is therefore circular rather than one-directional. Genetic and epigenetic changes can remodel three-dimensional structure, but the structure itself may also influence where alterations arise and how strongly they affect the cell. Regions of open, actively transcribed chromatin may experience different forms of replication stress or DNA damage from compact, inactive regions. The physical proximity of distant DNA segments may also increase the likelihood that breaks occurring in separate locations will be misrepaired together. A spatially organized genome could thus help shape the distribution of mutations and rearrangements that cancer evolution selects.
This feedback may help explain why some abnormalities become especially powerful during tumour development. A genetic alteration that appears modest when considered only at the sequence level may have a much larger effect if it changes a domain boundary or creates a new loop. Conversely, the same mutation could produce different outcomes in different cellular contexts, depending on the existing chromatin landscape and the regulatory elements available nearby. The review emphasizes that oncogenic capacity can sometimes be understood only by analysing the interaction between DNA sequence, epigenetic state and three-dimensional conformation.
The picture becomes even more complex inside individual tumours. Cancer is not usually a uniform population of identical cells; instead, it contains subclones with different mutations, epigenetic profiles and functional states. Their chromatin architectures may differ as well. Some cells may maintain highly active regulatory circuits that support rapid proliferation, while others may occupy more dormant or treatment-resistant states. This three-dimensional heterogeneity could influence how tumours evolve, spread and respond to therapy. A treatment that eliminates cells with one chromatin configuration might leave behind a subpopulation whose regulatory architecture enables survival and later regrowth.
Mapping these structures could eventually provide new approaches to cancer diagnosis and treatment. Technologies that measure chromatin contacts, such as chromosome-conformation methods, can reveal interactions across the genome that are invisible to conventional genetic tests. When combined with sequencing, transcriptomics and epigenomic profiling, these approaches may help identify abnormal enhancer–gene connections, disrupted domain boundaries or tumour-specific regulatory circuits. Such information could improve the classification of cancers and expose vulnerabilities that are not apparent from mutations alone. Therapies might one day target the proteins that establish or maintain harmful chromatin contacts, or exploit the dependence of tumour cells on particular three-dimensional configurations.
The authors present chromatin three-dimensional remodelling as both a cause and a consequence of oncogenic change. This view expands the definition of the cancer genome beyond a linear sequence of bases and toward a dynamic system in which location, accessibility and physical contact are essential parts of gene regulation. Major questions remain, including how stable abnormal architectures are across tumour cells, how they change during metastasis and treatment, and whether they can be measured reliably in clinical samples. Yet the emerging principle is clear: to understand why a cancer behaves as it does, researchers may need to read not only the genome’s letters, but also the three-dimensional shape in which those letters are folded.
Subject of Research: The role of three-dimensional chromatin architecture in cancer development, tumour heterogeneity, oncogenic regulation and potential diagnosis and therapy.
Article Title: Origins and consequences of oncogenic 3D chromatin remodelling
Article References: Franceschini, G.M., Georgakopoulou, K., Ciriello, G. et al. “Origins and consequences of oncogenic 3D chromatin remodelling.” Nature Reviews Cancer (2026). https://doi.org/10.1038/s41568-026-00969-1
Image Credits: AI Generated
DOI: 10.1038/s41568-026-00969-1
Keywords: Cancer biology, chromatin architecture, 3D genome, gene regulation, epigenetics, oncogenes, tumour suppressors, chromatin loops, genomic rearrangements, cancer heterogeneity, precision medicine
