In an article published in
Molecular Cell, scientists have discovered how the three-dimensional organization of DNA in our cells influences genes across multiple generations.
By manipulating the organization of DNA in fruit flies without altering its sequence, they triggered a change that persists over many generations. This discovery reveals a new form of inheritance, complementing that transmitted by the DNA sequence.
Beyond genes: the 3D organization of DNA influences their expression.
We are accustomed to the idea that the essence of who we are lies in our genes, which we inherit equally from each of our two parents. However, the information contained in our DNA sequence does not tell the whole story. In addition to this genetic material, so-called "epigenetic" signals play a crucial role in individual identity and are increasingly recognized as an integral part of the information passed from parents to their offspring.
The term "Epigenetics" refers to processes that affect gene expression without altering the DNA sequence and most often refers to a set of chemical modifications of DNA and associated proteins that activate or deactivate genes. A lesser-known but equally crucial element is the organization of genes in 3D space within the cell.
Deactivated genes, for example, can cluster together and form repressed groups that mutually silence each other. These contacts between regions of DNA that would normally be distant mean that even genes on different chromosomes can influence each other through actual physical interactions.
Flies and colors: an experiment that revolutionizes our view of biological inheritance.
In a new study, published in the journal
Molecular Cell, scientists demonstrated that physical contacts between two fruit fly genes trigger an epigenetic change in one of them that can be inherited from one generation to the next. This results in a striking change in the appearance of the flies, which have red or white eyes and pass this eye color on to their offspring for many generations.
In general, the mechanism that generates such contacts is complex and still poorly understood. In this case, scientists were able to show that a protein called GAF, which binds to both genes, initiates the process of epigenetic inheritance. A mutation in GAF eliminated these contacts, highlighting its key role in bringing together these normally distant regions of the genome.
The inheritance of non-genetic information across generations, a process known as transgenerational epigenetic inheritance, has been studied in fruit flies.
In this organism, the hemizygosity of the Fab-7 regulatory element is capable of triggering the inheritance of the histone mark H3K27me3 on a homologous locus on another chromosome, resulting in heritable epigenetic differences in eye color.
This article highlights the importance of PHO and GAF proteins in establishing and maintaining this transgenerational inheritance. These two proteins play essential roles, respectively, in recruiting the Polycomb repressive complex 2 (PRC2) and mediating interchromosomal chromatin contacts.
© Giacomo Cavalli Although these observations suggested that GAF-directed contacts were the key event leading to the inheritance of epigenetic information, this was not yet definitive proof. To achieve this, scientists recreated these contacts artificially by designing and expressing a protein capable of binding to the two genes of interest (and only these genes).
This protein thus mimicked the role of GAF by binding to both genes to link them together. Forcing these contacts in this way produced the same effect as a natural increase in interactions and led to the inheritance of eye color over multiple generations.
This experiment demonstrated the essential role of the three-dimensional organization of the genome in this process, implicating it for the first time in the inheritance of epigenetic information. This new publication proposes a novel mechanism to explain how certain epigenetic signals, which might otherwise be lost between generations, can become transmissible.
This could contribute, alongside genetics, to the information we inherit from our parents and pass on to our children.
Furthermore, scientists have developed a synthetic biology system to induce chromatin contacts
in vivo. They demonstrated that these contacts can establish transgenerational inheritance, showing that the simple contact between two loci can induce heritable gene expression reprogramming over multiple generations.
Reference
Interchromosomal contacts between regulatory regions trigger stable transgenerational epigenetic inheritance in Drosophila.
Fitz-James, M.H., Sabaris, G., Sarkies, P., Bantignies, F. & Cavalli, G.
Molecular Cell (2024).
DOI:
10.1016/j.molcel.2024.11.021