Researchers discover 3D chromatin structure may affect the immune response

Researchers studying the body's ability to produce antibodies for defense against novel viruses have found that the 3D structure of chromatin controls which gene segments are available for recombination.

The research, which was conducted by a team of scientists from different agencies and universities, including the National Institute on Aging in Baltimore, studied how the diversity (DH) and variable segments (VH) find their targets during the recombination process.

Lymphocyte antigen receptors, or immunoglobulins (Igs), are composed of two heavy chain (IgH) and two light chain (IgL) polypeptides. The ability of B lymphocytes to recognize and mount immune responses against a wide variety of pathogens lies in the diversity of Igs expressed on their cell surface.

It is certain features of the recombination process that produce this important diversity of IgH genes, which is not encoded in the genome. This type of recombination is called VDJ recombination and allows the body to adapt and battle novel pathogens.

Importantly proper IgH gene assembly relies on participation of all relevant gene segments, including diversity (DH) and the variable (VH) regions.

The researchers, in their paper published in ScienceAdvances, state the rules under which the two different segments operate and rearrange as the recombination process takes place.

"Diversity [DH] gene segments rearrange first, followed by variable [VH] gene rearrangements," the authors wrote.

DH gene segments recombine by deletion of the intervening DNA within a RAG1/2 scanning domain. This process relies on the Eμ interactions with IGCR, which sequesters the DH gene segment to a certain region, isolating it from other potential recombination opportunities. The second step of IgH gene assembly is unique from the first step. The VH segment finds its target likely by diffusion and then either inversion or deletion completes the recombination process.

"Here we provide evidence that each rearrangement step is guided by different rules of engagement between rearranging gene segments," the authors wrote. "We propose that VH gene segments find their targets by distinct mechanisms from those that apply to DH gene segments."

This combinatorial shuffling to produce antibody genes that can target any pathogen happens during the development of the immune cells (B-cells). In this study, the scientists reveal that 3D chromatin structure affects the availability of these gene segments and, therefore, influences the recombination process.