Physics and genetics together to understand DNA organization and gene regulation

The scientific journal Nature has published a study presenting the results of the NIH (National Institutes of Health, USA) 4D Nucleome Project, which provides a detailed description of the spatial organization of human DNA based on the integration of interdisciplinary methods ranging from genomic and imaging technologies to theoretical physics models and computational approaches. The work represents a fundamental basis for understanding the link between the physical arrangement of chromosomal DNA within the cell nucleus and the regulation of the genes it contains. The study is conducted within the framework of the activities of the Scientific Commission for Theoretical Physics (CSN4) of the Italian National Institute for Nuclear Physics and, in particular, within the specific initiative “BioPhys”.

The 4D Nucleome (4DN) Project

The three-dimensional organization of human DNA plays a fundamental role in controlling the use of genetic information. The 4D Nucleome Project aims to study this organization in space and time, the fourth dimension. The cell nucleus contains DNA in the form of 23 pairs of strands called chromosomes, which include the genes necessary for the production of proteins involved in the vital functions of the cell. The way DNA is organized, stored, and made accessible within the nucleus is crucial for human health and for understanding how alterations in this organization may be associated with the development of diseases, such as cancer, or influence the response to infectious agents.

The efforts of the research consortium have also made it possible to identify some fundamental physical mechanisms that control the complex spatial organization of the genome, such as phase separation processes, initially identified by pioneering studies from Mario Nicodemi’s group using Statistical Mechanics models of the nuclear environment.

“Having identified the physical mechanisms that govern the system”, emphasizes Mario Nicodemi, professor at the University of Naples Federico II and INFN associate, “we can, for the first time, understand, using physics-based models, how alterations in the spatial organization of the genome lead to the onset of cancer or other genetic diseases”.

For his scientific discoveries at the frontier between physics and biology, Mario Nicodemi received the Einstein BIH Fellowship from the Einstein Foundation in Berlin in 2016 and, in 2022, the Occhialini Medal from the Italian Physical Society (SIF) and the UK Institute of Physics (IOP).

Finally, the study explores the use of machine learning and artificial intelligence methods to predict chromosomal conformation from the DNA sequence and to identify regulatory elements involved in genome folding. These approaches provide new tools to link genomic architecture to biological processes and represent a foundation for future studies on the 4D nucleome.

Link to the paper:
https://www.nature.com/articles/s41586-025-09890-3