DNA origami: a new frontier in epigenetic inheritance across generations
In a collaboration between two labs spanning both sides of the English Channel, scientists have discovered a new way in which the organisation of DNA within our cells affects genes for generations. In this piece, Max Fitz-James, the lead author on the project, working between the Sarkies lab here in Biochemistry and Giacomo Cavalli’s group at the Institute of Human Genetics in Montpellier, describes the work and its implications:
Figure: Transgenerational Epigenetic Inheritance of eye colour
We have become used to the idea that much of who we are can be found within our genes, which we inherit in equal parts from each of our two parents. However, this type of information locked within our DNA sequence is not the whole story. In addition to this genetic material, epigenetic signals are an essential part of individual identity and are increasingly found to be part of the information passed down from parent to offspring.
“Epigenetics” refers to processes that affect the expression of genes without changing the DNA sequence, and most often denotes an array of chemical modifications to the DNA and associated proteins which turns genes on or off. A less well-known but also crucial element is the organisation of genes in 3D space within the cell. Genes that are turned off, for instance, can group together and form repressed clusters that keep each other off. These contacts between regions of DNA that would ordinarily be far away mean that even genes on different chromosomes can influence each other through actual physical interactions.
In the work just published at https://www.cell.com/molecular-cell/fulltext/S1097-2765(24)00946-8, I discovered that physical contacts between two fruit fly genes trigger an epigenetic change in one of them that can be inherited across generations. This leads to a striking change in the appearance of the flies, specifically in the colour of their eyes, a trait which they pass on to their offspring for many generations.
What is responsible for this change? I suspected that this might be due to a protein called GAF. GAF can bind to DNA sequences found in the two genes, so it might be able to act as a bridge to join the two genes together. Removing these binding sites also prevented the contacts from forming, strongly suggesting GAF’s involvement. Although this seemed like a likely explanation, I wanted to test it directly. To do this I tried to mimic what GAF might do. I designed a protein in the lab that would bind to our two genes of interest and introduced this into the flies. Amazingly, this had exactly the same effect, leading to a change in eye colour that was transmitted for many generations!
I think my work is very important because it implicates for the first time the role of the 3D organisation of the genome in epigenetic inheritance. This provides a new mechanism to explain how some epigenetic signals which might otherwise be lost between generations can become heritable and potentially contribute, alongside genetics, to the information we inherit from our parents, and pass on to our children.
Max Fitz-James and Peter Sarkies
5th December 2024
