In 2003, scientists completed the mapping of the human genome – they determined the entire sequence of genetic letters that make up our DNA. However, we now know the sequencing map only partly explains how the genome works and that the way DNA is folded and packed to form chromosomes also matters.
Over the last decade, studies of the spatial architecture of chromosomes reveal they are divided into “topological domains” – sections of DNA that are in contact with each other more often than their neighbors in the sequence map of the genome.
For example, imagine the sequence map of DNA as a long necklace of beads. When you wind the necklace around your hand, some beads that are far apart along the necklace are brought closer together.
It is becoming apparent that the folding and packing of DNA into chromosomes to fit inside the nucleus of a cell is not just a matter of efficiency. Chromosomes are highly structured complexes of DNA and proteins organized to allow access for gene expression and DNA processing.
Now, a new paper published in the journal Molecular Systems Biology reports how an international team has produced comprehensive 3D maps of the spatial organization of the mouse genome, from embryonic stem cells to fully developed neurons.
The scientists, from Germany, Italy, Canada and the UK, believe that such maps will help pinpoint genes that are involved in hereditary diseases.
Study leader Ana Pombo, a professor from the Max Delbrück Center in Berlin-Buch in Germany, where she heads a group studying the relationship between gene activity and DNA folding, explains the importance of the 3D organization of DNA:
“The complex spatial folding of the DNA of the chromosomes controls the activity of genes.”
The mouse genome comprises 20 pairs of chromosomes, each packed in a highly ordered manner in the nucleus of each cell.
Before the new study, knowledge about the architecture of the mouse genome was limited to the spatial structure in and around topological domains. But this did not explain how the domains interact with each other and whether such interactions are important for gene function, the researchers note.
For their study, the team took a detailed look at how the entire mouse DNA is folded in the chromosomes and which regions preferentially interact with each other.
As a model, they investigated the development of the mouse neuron, from its beginnings as an embryonic stem cell, through the progenitor cell stage, until its final stage as a differentiated neuron.
For each of these stages of cell development, they analyzed interaction maps – called “Hi-C data” maps – that show which regions of folded DNA are in contact with each other inside each chromosome.
Using the Hi-C data approach, the team built up a matrix of contacts for each of the 20 chromosomes in all three cell stages of the mouse neuron.
The results reveal that chromosome domains consist of larger “meta-domains” whose folding is not random – an important finding of the study, as Prof. Pombo explains:
“Various regions on a chromosome come together because they have something in common. Regions with similar functional properties contact each other, for example, genes that are active or that are regulated by the same mechanism.”
She says this is the first time they have been able to show that specific contacts take place between domains that sequentially lie far apart in chromosomes.
The team represents this interaction as a tree-like hierarchy of domains that shows which regions are in contact with each other.
When they compared the tree diagrams of the three stages of neuron development – the embryonic stem cell, progenitor cell and differentiated cell – they found most of the long-range contacts persisted, but other regions formed new contacts based on common features.
One of the first authors of the study, Dr. Markus Schüler, a researcher in Prof. Pombo’s group, says:
“Changes in gene activity correlate with changes in the spatial organization.”
The team believes their map of contacts will help find causes of genetic diseases. For example, it could help pinpoint changes in chromosome structure that play a role in cancer, or it could help identify genes behind congenital conditions.
While such discoveries have already been made in the sense that the genes responsible have been identified, what the 3D contact maps will help with is understanding the nature of the link between the gene and disease.
It could be, for example, that it is the interaction rather than the gene itself that has become dysfunctional.
The 3D maps offer the chance to look not only at the gene but also the other regions of DNA the gene is in contact with.
Prof. Pombo concludes:
“Our maps increase the pool of targets on DNA that might be affected by a single mutation.”
The team in Berlin now plans to use the maps to study skeletal diseases and neurological disorders, such as autism.
Earlier this year, Medical News Today reported how a group from another research center in Germany discovered that cells compact their DNA when starved of oxygen and nutrients. This starved state is seen in many of today’s common diseases like heart attack, stroke and cancer.