Dynamic 4D map of the human genome created

A detailed integrated map of the human genome's three-dimensional (3D) structure over time shows how DNA structure is linked to gene activity.

An international team of scientists has published a 3D map of the human genome, showing how its shape changes over time to create a four-dimensional (4D) view of DNA inside living cells. The researchers analysed two human cell types – embryonic stem cells and connective tissue fibroblasts – combining multiple genomic techniques that measure how DNA folds, loops, and positions itself within the nucleus. Their results, published in Nature, highlight how genome structure and movement are closely associated with gene function.

'Understanding how the genome folds and reorganises in three dimensions is essential to understanding how cells function,' said co-lead author Professor Feng Yue from Feinberg School of Medicine Northwestern University, Chicago, Illinois. 'These maps give us an unprecedented view of how genome structure helps regulate gene activity in space and time.' 

The researchers combined multiple types of genomic data into integrated datasets, which were then used to generate time-resolved maps showing how DNA folding, gene activity and nuclear organisation are linked. These maps include loop formation, domain organisation, and nuclear positioning of genomic regions.

Conducting specific experiments that detect physical contacts between distant regions of DNA, they assembled catalogues of over 140,000 DNA looping interactions in each cell type, revealing how DNA loops, folds and twists inside the nucleus to bring genes into contact with regulatory elements or, in some cases, keep them apart. These patterns of folding are associated with differences in gene activity, and how cells carry out essential tasks like growth and division. The study shows that, rather than being a static sequence of base pairs, the genome shows coordinated structural organisation: its physical form is closely linked to function.

In parallel, computational models were developed to predict aspects of genome folding from DNA sequence. Because most disease-associated variants lie outside protein-coding regions, these models may help scientists understand how genetic changes could influence DNA folding and gene regulation.

'Since the majority of variants associated with human diseases are located in the non-coding regions of the genome, it is critical to understand how these variants influence essential gene expression and contribute to disease,' Professor Yue added. 'The 3D genome organisation provides a powerful framework for predicting which genes are likely to be affected by these pathogenic variants'.

The 4D nucleome – the three-dimensional organisation of the nucleus in space and time – may offer new insights into how we understand gene regulation and disease. The team plans to extend their research to include more cell types, developmental stages and disease states, building a more complete picture of how the genome's shape influences biology and health.

All the data generated in this project are made publicly available to support further research exploring links between genome structure and biological function.