More than 40 years ago, researchers discovered V(D)J recombination, a critical process for the human immune system that produces a diverse repertoire of antibodies to ward off antigens and other potential threats.
However, what has remained an unknown is how the initiation of the V(D)J recombination process occurs, according to Yu Zhang, MD, PhD, an assistant professor in the medical school’s Department of Biomedical Sciences and a researcher in the Center for Immunobiology.
Now, a new study published in Nature in September provides an answer to what Dr. Zhang says has been “a central question” about V(D)J recombination.
“I think we provide an answer for this question or at least a major step toward understanding this question,” said Dr. Zhang, who is listed as first author on the new study, “The fundamental role of chromatin loop extrusion in physiological V(D)J recombination.” “In a more generalized way, we are trying to understand or provide insights about the mechanisms of how this process is making the diverse antibody repertoires.”
Dr. Zhang said the new study was the result of “a team effort” that began four years ago and was led by Frederick Alt, PhD, director of the Program in Cellular and Molecular Medicine at Boston Children’s Hospital and the Charles A. Janeway Professor of Pediatrics in the Department of Genetics at Harvard Medical School.
Prior to coming to WMed in 2018, Dr. Zhang was a postdoctoral fellow in Dr. Alt’s lab and took on the project “Mechanisms that Control Antigen Receptor Variable Region Exon Assembly.” Her research revealed many important mechanistic insights on the nature of RAG-mediated illegitimate V(D)J recombination that leads to oncogenic lesion in B and T cell lymphoma.
Dr. Zhang’s research also implicated a novel mechanism of RAG targeting via linear scanning on DNA to locate substrates and demonstrated the physiological importance of RAG scanning in normal V(D)J recombination during antigen receptor assembly.
Dr. Zhang said the team’s study published in Nature provides “very clear evidence” that formation of chromatin loops, known as loop extrusion, is the driving force behind the targeting process performed by the enzyme known as RAG that helps initiate V(D)J recombination.
Dr. Zhang said the study revealed new insights in broader genome structure studies to examine genome loops and the function of genetic element interactions. Moreover, she said they can be applied to develop new therapeutic approaches to target pathogenic loops in cancer and developmental disorders.
“It will be exciting to employ this knowledge to direct specific antibody generation to be used in certain disease treatment such as HIV vaccine design,” Dr. Zhang said. “This also provides an approach to study the impact of genome structures on immune processes in follow-up studies.”