Left: staining for H3K27me3, which marks inactive DNA, on a nucleus of a wildtype embryo consisting of two cells. Right: staining for H3K27me3, which marks inactive DNA, on a nucleus of an embryo consisting of two cells, where H3K27me3 regions have been tethered to the nuclear periphery. Credit: Isabel Guerreiro.

Researchers have gained new insights into the mechanism behind the spatial organisation of DNA within the cells of early embryos.

When an embryo is first formed after fertilisation, each cell has the potential to become any cell type of the body. The researchers from the Hubrecht Institute’s Kind Group have studied the spatial organisation of DNA that is so particular to these early developmental stages.

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 fertilisation, each cell can become any type of cell, including brain cells or even placenta cells.  

Active and inactive

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 organisation 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 organisation 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 organisation of DNA at length, much is still unclear about how this organisation is first established during embryonic development. 

Unique DNA organisation

To understand embryo development better, the researchers wanted to know how the epigenome regulates the organisation 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, explained: “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 analyse the spatial DNA organisation in individual cells from early embryos.

High levels of modification

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.

Guerreiro said: “This suggests that the presence of this modification repels the DNA regions from the nuclear edge.

“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 organisation of DNA regions in the cell nucleus of early embryos.”

Major cause

The researchers have found a major cause for the atypical spatial DNA organisation 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 concluded: “Uncovering the mechanism behind the unusual nuclear organisation that characterises the early embryo has the potential to improve regenerative medicine strategies and human in vitro fertilisation outcomes.”

The paper is published in Nature Genetics.