Representative single-cell 3D structures of chromosome 1 in H1 (left) and HFFc6 (right) cells. Credit: Nature (2025). DOI: 10.1038/s41586-025-09890-3

One of the most detailed 3D maps of how the human chromosomes are organized and folded within a cell’s nucleus is published in Nature.

Chromosomes are thread-like structures that carry a cell’s genetic information inside the nucleus. Rather than existing as loose strands or only as the familiar X-shapes seen in textbooks, chromosomes fold into specific three-dimensional forms. How they fold, the structures they form, and their placement play crucial roles in maintaining proper cellular functions, gene expression, and DNA replication.

The team involved in the 4D Nucleome Project, whose goal was to understand the 3D organization of human chromosomes in the nucleus and how it changes over time, identified over 140,000 DNA looping interactions in human embryonic stem cells and fibroblasts. They also presented computational methods that can predict genome folding solely from its DNA sequence, making it easier to determine how genetic variations—including those linked to disease—affect genome structure and function.

Mapping the loops in 3D space

The Human Genome Project gave the first glimpse of a human genome sequence—the complete list of DNA molecules that make up human chromosomes— at the turn of the 21st century. Ever since, scientists have been looking for a way to zoom in on the complex structures of the precious genetic material carried within our cells.

While genome sequences reveal which genes are present, they do not explain how those genes are switched on or off. To understand this, we need a clearer picture of chromosome architecture and a precise map of the arrangement of DNA within the nucleus and its interactions with other nuclear structures.

Chromosomes tend to organize themselves into 3D structures inside a cell’s nucleus, where they store the DNA by looping it around histone proteins and bringing the segments together using cohesin proteins.

Overview of the approach to generate and integrate genomic data on the 4D nucleome. Credit: Nature (2025). DOI: 10.1038/s41586-025-09890-3

These structures, also known as chromatin loops, are fundamental to how the genome organizes itself in a 3D space. By bringing separate regions of DNA into contact, chromatin loops promote interactions required for gene regulation and expression.

So, the researchers of this study decided to look further into these looping interactions by investigating the 4D nucleome, which involved a multi-step approach to map the 3D organization of the human genome into two human cell types: H1 embryonic stem cells and immortalized foreskin fibroblasts.

The team began with a series of laboratory tests, known as genomic assays, to measure how frequently different regions of DNA interact or come into close proximity, as well as interactions involving specific proteins.

The data from various assays were integrated to develop an Integrative Genome Modeling (IGM) platform comprising 1,000 distinct 3D models of the genome for individual cells. They also used these data to train deep learning models that predict the 3D folding of the genome from the DNA sequence alone.

Bringing together data from all the applied techniques, the team built integrated genomic datasets of the 4D nucleome. They cataloged more than 141,365 regulatory looping interactions for the stem cells and 146,140 for the fibroblasts, and created single-cell models that show gene interactions with distant regulatory elements throughout three-dimensional space.

The researchers highlight that these models could reveal the DNA sequences that guide genome folding and enable the prediction of genetic variations that reshape this 3D structure. Continued exploration along this line could uncover key insights for scientists and clinicians working on genetic disorders.

Written for you by our author Sanjukta Mondal, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You’ll get an ad-free account as a thank-you.

More information: Job Dekker et al, An integrated view of the structure and function of the human 4D nucleome, Nature (2025). DOI: 10.1038/s41586-025-09890-3

Elzo de Wit, Systematic maps reveal how human chromosomes are organized, Nature (2025). DOI: 10.1038/d41586-025-03808-9

Journal information: Nature

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Citation: Scientists chart over 140,000 DNA loops to map human chromosomes in the nucleus (2025, December 22) retrieved 22 December 2025 from https://phys.org/news/2025-12-scientists-dna-loops-human-chromosomes.html

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