3D Genome Analysis Discloses Mechanism Behind Antibody Diversity

[seqadmin]

The human immune system employs a multitude of antibodies to combat infections. Remarkably, this vast array stems from the recombination of around 200 genes. However, the mechanism that achieves this incredible diversity has remained elusive.

Researchers at the Babraham Institute have now elucidated a process where varying gene combinations converge in close physical proximity, leading to the creation of distinct antibodies in each B cell. By harnessing advanced 3D modeling and techniques, they discerned the DNA folding patterns in mouse B cells. Intriguingly, they observed that the organization of antibody DNA differs across cells.

This mystery of how B cells produce an extensive array of antibodies to fend off various pathogens has long puzzled immunologists. The Babraham Institute team, integrating knowledge from immunology, biophysics, bioinformatics, and 3D genome analysis under the guidance of Dr. Anne Corcoran, identified that the 3D DNA structure in mouse B cells plays a pivotal role in this process. This organization permits genes, even those located distantly, to coalesce during antibody formation, leading to a robust defense mechanism. Contrary to expectations, each B cell displays a distinct genomic folding pattern, offering limitless gene combination possibilities.

Dr. Anne Corcoran commented, “We wanted to understand the mechanisms behind antibody variety. One way the cell achieves this is cutting and pasting from a suite of options for the antibody genes, but the puzzling thing is genes that are far away from the location of this event are used just as often as ones close by, so there must be some way of bringing everything together and making sure that everything needed is at hand.”

Previously, the scientific community lacked the necessary tools to probe this process. While some believed DNA organization to be malleable, others theorized the existence of consistent folding principles. Thanks to advanced methodologies from Corcoran's lab, this debate has now been settled.

The team adopted an advanced sequencing method to capture intricate DNA configurations in B cells. This method builds on the enriched Hi-C genome analysis technique, which pinpoints direct chromosomal contacts. Armed with this comprehensive data, the team could understand DNA looping and chromosomal connections more effectively. Collaborating with Dr. Luca Giorgetti’s laboratory at the Friedrich Miescher Institute in Basel, Switzerland, they crafted 3D gene structure simulations to substantiate their conclusions.

In addition to charting antibody gene interactions, associations between essential genes crucial for B cell development were also identified. Such chromosomal contacts potentially play a vital role in the synchronized gene expression regulation during B cell maturation.

Dr. Corcoran further added, “We found that the antibody genes were in close proximity to a small proportion of other genes on different chromosomes. Once we characterized them we found that these genes were associated with B cell development. And that was very interesting to see because if we apply this approach to other cell types we might be able to find important chromosomal interactions that are unique to those cell types.”

The team also hypothesizes that DNA folding alterations could influence the diversity of antibodies over time. As we grow older, the spectrum of antibodies produced narrows due to B cells opting for a limited gene pool, especially sidelining the distant genes. Changes in DNA folding might render certain genes inaccessible, hence not chosen for antibody formation. A significant direction for future research will involve studying the 3D DNA organization of genes in aging B cells.

Read the full article here.