New research tracks how cells prepare gene regulatory decisions that will define their fate during the earliest stages of human development. The study reconstructs a timeline of chromosome folding that brings remote DNA regulatory regions into physical contact with genes they control. This work, from a team at the MRC Laboratory of Medical Sciences (LMS) and Imperial College London, with collaborators from the Babraham Institute in Cambridge, shows that some of these contacts form long before genes are activated, persist through later development, and may help pre-select the future gene targets of these regions. These findings highlight how the genome’s 3D structure helps shape cell identity and could offer clues to how developmental disorders arise.
By Emily Armstrong
June 8, 2026
Time to read: 4 minutes
Every cell in the body contains the same set of genes. Deciding which gene to express and when determines the unique identity of the different cell types in our bodies. Regions of DNA called enhancers play a key role in gene regulation by serving as “molecular switches” that turn genes on and off in the correct cell type and conditions. They are often far away on the DNA thread from the genes they control, and need to come into proximity with them through DNA looping within the 3D space of the nucleus. The research, published in Cell Reports, examines how, when, and why these contacts are established during early human development.
Using a high-resolution technique, Capture Hi-C, the team mapped enhancer chromosomal contacts in human pluripotent stem cells transitioning from the naïve to primed state. This transition corresponds to a critical time window in early human embryogenesis, when the stem cells undergo crucial changes in their gene expression, chromatin state and developmental potential. During this time, many enhancers controlling the genes responsible for embryonic development acquire an intermediate, ‘poised’ chromatin state between ‘on’ and ‘off’ to prepare them for action, and make physical connections with their future target genes.
The results paint a dynamic picture, with the ‘poising’ of enhancers and their ‘looping over’ to target genes in the 3D space of the nucleus happening at different times in different contexts. But a fundamental pattern is that many enhancers form chromosomal contacts with genes long before these genes are turned on in development.
Importantly, the pre-formed contacts between enhancers and genes are often retained until genes must activate later. The study suggests that this early wiring may help pre-select genes for rapid activation by enhancers at the right time and in the right cells, orchestrating developmental decisions. To prove that, the team artificially switched on a poised enhancer using CRISPR targeting. They showed that this activated a gene already connected to this enhancer in 3D, but not one located closer to it along the chromosome, but lacking such contact.
This work, highlighting how 3D genome architecture shapes gene expression programmes in early human development, complements another recent study from the institute, demonstrating the 3D genomic blueprint of the first steps of embryo development in Drosophila.
Dr Mikhail Spivakov, Head of the Functional Gene Control Group and the study’s senior author, said: “This analysis helps us understand the role of the 3D genome in shaping developmental decisions. Even before any gene expression has happened, the genome is already set up to enable the right enhancers to activate. This is a fundamental process that helps define cell identity across the life course. This work opens a research direction to explore whether missteps in this process underpin developmental abnormalities.”
Dr Marina Nocente, the study’s joint first author, said: “Setting the correct genome architecture allows cells to orchestrate a precise sequence of genetic activity to develop from a single fertilised egg to a fully-formed organism. Understanding how 3D genome organisation allows for healthy development illuminates fundamental human biology and may pave the way to a better understanding of disease”.
Dr Maria Rostovskaya, a study co-senior author and currently a group leader at the Gurdon Institute at Cambridge University, said: “Our study demonstrates the power of stem cell models for understanding early human development. There is growing evidence that before cells specialise, they undergo important molecular preparatory stages, including the organisation of the genome into 3D structures that shape future gene activity. Understanding these early processes could provide important insights into human embryogenesis and support the development of improved in vitro cell systems for biomedical research.
This study was performed in collaboration with the Babraham Institute in Cambridge, and funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the Wellcome Trust. The research was led by Drs Marina Nocente, Monica Della Rosa and Mikhail Spivakov, with collaborators, Drs Maria Rostovskaya and Peter Rugg-Gunn, from the Babraham Institute in Cambridge.
Read the full publication: https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00480-8
This article was written by Anthony Lewis, Freelance Science Multimedia Producer