Hongli Hu, Ph.D., Postdoctoral Fellow Boston Children's Hospital

One way the immune system protects us from diverse pathogens is by generating billions of B lymphocytes, each armed with a different form of pathogen-recognizing B cell receptor (BCR).  Together the billions of different BCRs on different B cells recognize almost any encountered pathogen. When a B cell recognizes a particular pathogen, it fights it by secreting its BCR as an antibody. Antibody subunits have a pathogen-recognizing sequence termed variable regions that are different in each BCR. The number of different BCRs in our body is far greater than could be encoded by our genes. Developing B cells accomplish this genetic feat by cutting and pasting genetic cassettes together into sequences that encode variable regions by a process termed V(D)J recombination. As these genetic cassettes are spread across long chromosomal distances, the mechanism by which they find each other during V(D)J recombination was a mystery. It was recently discovered that developing B cells harness a genetic process termed chromatin loop extrusion to reel widely separated variable region cassette-containing chromosomal regions past each other at a genetic site where they are cut and pasted. 

Dr. Hu proposes new experiments that will reveal in detail how this remarkable chromosomal topology-altering process is regulated to bring diverse variable region cassettes together. The work will elucidate fundamental mechanisms that generate antibody diversity and how the process goes awry to generate genomic rearrangements in cancers of developing B cells. Proposed studies should also inform new approaches to generate therapeutic human antibodies against cancer and other diseases.

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