Control of gene expression and recombination during lymphocyte differentiation

The grand mixture of lymphocyte genes

B and T lymphocytes of the adaptive immune system are able to fight a multitude of foreign agents, also called antigens. This property stems from their ability to be equipped with sensors potentially as diverse as the antigens themselves. This diversity is achieved through the juxtaposition of random pieces of genes, a multi-step recombination that generates an infinite set of sequences, of which only the most useful are exploited by mature lymphocytes. Ultimately, each of these sequences encodes a receptor unique for each cell, allowing it to bind a single antigen with great specificity.

The identity of lymphocytes, as of all cells of the body, is determined by the activation or inhibition of specific genes in the cell type: this explains why all the cells of an individual are not identical even though they contain exactly the same DNA (i.e., the same genetic heritage). The team of Pierre Ferrier is trying to understand the mechanisms that regulate the recombination of genes in the lymphoid lineage, and more generally, those that activate these genes or maintain them silent, mechanisms commonly referred to as "epigenetics”.

 

Our DNA is not stored passively in the form of chromosomes: it is organized around a dynamic complex of proteins (chromatin) that can make available, or not the genes contained in the cell nucleus.
In locally unpacked chromatin (called open), the DNA becomes accessible to factors that activate genes. Where the chromatin is compacted (and therefore closed), the genes are inaccessible and remain off. Thus, the expression of genes can be modulated in time and space without altering the primary sequence of DNA. 

The dynamics of the DNA in lymphocytes,
at the interface of biology, mathematics, and one day ... physics.

The team of Pierre Ferrier is interested in studying the dynamics of DNA using three approaches: "Part of the team focuses on the study of multi-cell differentiation and control of expression and recombination of genes that encode their receptors," explains Pierre Ferrier, "another group is interested in deregulation of this system and its pathological consequences, particularly in the development of cancers. Finally, we are working with mathematicians to build models and develop tools adapted to the integration of the biological data we generate."

Indeed, the mechanisms of chromatin remodeling that enable the recombination of genes of lymphocytes involves the spatiotemporal coordination complex of so many factors that the study systems themselves need to be rethought. This "theoretical biology" also feeds the information available in public databases, which are integrated with the findings of the team to enrich and consolidate them.

"There is always a mathematical rule to predict the behavior of a population, be it a set of genes," says Pierre Ferrier. "In our case, we apply these models to understanding the regulation of gene nodes, which are central to the development of the immune system. But the same basic nodes are the ideal "target" of deregulation and their dysfunction has a strong impact that can lead to the cell becoming immortal, i.e., the loss of control, and therefore cancer."

In the medium term, Pierre Ferrier believes that research in biology will find an echo in a new field: "Physicists are questioning more and more the forces involved in the field, so that the biological system works," he says. "It’s not possible that factors that meet and interact to trigger a biological response are dependent on random motion: there must be forces or energies that guide their movement toward each other."

Much more than the primary sequence of human DNA that since 2001 is no longer a secret, it is in genome dynamics that reside the great mysteries of the development of our immune system and beyond that, the functioning of our body.