New insights into DNA organization during embryonic development

Researchers from the Kind Group have gained new insights into the mechanism behind the spatial organization of DNA within the cells of early embryos. When an embryo is first formed after fertilization, each cell has the potential to become any cell type of the body. The researchers have studied the spatial organization of DNA that is so particular to these early developmental stages. The paper was published in Nature Genetics on September 16th, 2024. 

Every cell in our body contains the same DNA. This DNA contains the genetic information that serves as a blueprint for making the proteins necessary for the functioning of the cell. Although all cells have the same DNA, they activate only specific parts of it. As a result, cells develop into different cell types and perform a variety of functions. This is especially relevant during embryo development. When the embryo is first formed after fertilization, each cell can become any type of cell, including brain cells or even placenta cells.  

DNA organization in the nucleus  
DNA is located in the cell nucleus where it is folded into active and inactive compartments. Regions of the DNA that are located at the edge of the cell nucleus are normally more densely packed and inactive. This spatial DNA organization is important because it determines which parts of DNA are active. This varies per cell type, such as between blood cells and brain cells. In cells with different functions, specific parts of the DNA change their packaging and spatial organization within the nucleus. This results in different genes being turned “off” and “on”. These changes determine which genes are active and give the cell its identity. Such processes that affect the activity of genes without changing the DNA itself are the epigenome of the cell. Although scientists have investigated the spatial organization of DNA at length, much is still unclear about how this organization is first established during embryonic development. 

Unique DNA organization in early embryos 
To understand embryo development better, the researchers wanted to know how the epigenome regulates the organization of DNA. In an earlier study, researchers from the Kind group have shown that positioning of DNA regions near the nuclear edge during the first days of embryo development is highly unusual during early embryo development. This might explain how those first cells can be so flexible in what they can become. Isabel Guerreiro, co-first author of the study, explains: “With this work we aimed to understand what causes the unusual positioning of DNA regions at the edge of the nucleus during early mammalian development. This is often difficult to study, because we can only collect a few cells from early embryos.” To study these cells, the researchers used techniques they had previously developed. These techniques enabled them to analyze the spatial DNA organization in individual cells from early embryos.  

Causes of unique DNA organization in early embryos 
Using these techniques, called scDam&T-seq and EpiDamID, the researchers found that DNA regions that are not located near the nuclear edge have high levels of a specific modification in the proteins around which the DNA is wrapped. “This suggests that the presence of this modification repels the DNA regions from the nuclear edge”, Guerreiro explains. “However, it is not only the presence of this protein modification that decides where DNA regions are located. We found that the balance between the ‘repellent’ protein modification and an intrinsic attraction of the DNA sequence to the nuclear edge, determines the unusual organization of DNA regions in the cell nucleus of early embryos.”  

Understanding embryo development 
The researchers have found a major cause for the atypical spatial DNA organization inside the nucleus of early embryo cells. These findings represent a major step toward understanding healthy embryo development and uncovering the mechanisms that enable these cells to differentiate into a wide variety of cell types. Guerreiro tells: “Uncovering the mechanism behind the unusual nuclear organization that characterizes the early embryo has the potential to improve regenerative medicine strategies and human in vitro fertilization outcomes”.  

Publication
Antagonism between H3K27me3 and genome–lamina association drives atypical spatial genome organization in the totipotent embryo. Isabel Guerreiro*, Franka J. Rang*, Yumiko K. Kawamura, Carla Kroon-Veenboer, Jeroen Korving, Femke C. Groenveld, Ramada E. van Beek, Silke J. A. Lochs, Ellen Boele, Antoine H. M. F. Peters, Jop Kind. Nature Genetics, 2024.

*these authors contributed equally to this work

About Jop Kind
Jop Kind is group leader at the Hubrecht Institute, professor by special appointment of Single Cell Epigenomics at the Radboud University Nijmegen and Investigator at Oncode Institute.

About the Hubrecht Institute
The Hubrecht Institute is a research institute focused on developmental and stem cell biology. Because of the dynamic character of the research, the institute as a variable number of research group, around 20, that do fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit www.hubrecht.eu.