New insights on how chromatin scanning generates diverse antibody repertoires

Hai qiang Dai and Hongli Hu.

Co-authors Hai Qiang Dai and Hongli Hu. Photos courtesy of Children’s Hospital

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Researchers in the laboratory of Frederick Alt of the Howard Hughes Medical Institute and Program in Cellular and Molecular Medicine (PCMM) at Children’s Hospital Boston made a groundbreaking discovery at the nexus of chromatin biology and immunology.  Their work, recently published in Nature, showed that physiological deregulation of the WAPL chromatin-maintenance factor allows developing B lymphocytes to scan linearly through very long chromosomal loops to find and join gene segments that form diverse antibody repertoires.

Recently the Alt group discovered that V(D)J recombination and IgH class switch recombination (CSR), two discrete mechanisms of programmed genetic rearrangement in lymphocytes, both critical for adaptive immunity, are mechanistically driven by a basic process associated with management of the architecture of chromosomal genomes: chromatin loop extrusion (“Chromatin loops unlock antibody class switching”).

The implications of this research are potentially relevant to mechanisms of immunodeficiency and auto-immunity due to the impact of this mechanism on generating antibody diversity, as indicated by effects of mutations of cohesin complex factors being related to such diseases.

The developmental regulation of cohesin loop extrusion processivity will likely be an important mechanism by which other large genetic loci harness biological activities over long chromosomal distances.

The findings also provide further insights into how cohesin-mediated loop extrusion can contribute to mechanisms of oncogenic genomic translocations/deletions in early B and T lymphocyte cancers. These and related earlier findings have provided a basis for the Alt lab to generate novel humanized mouse models for HIV1-Vaccine testing and for broadening the activity, or discovery, of novel therapeutic antibodies.

The paper intriguingly suggests that much more is to be learned. Ongoing studies will further elucidate this new, long-range chromatin-based mechanism of developmental gene regulation.