Early B- and T-cell development is contingent on V(D)J rearrangement, a process by which antigen receptors are assembled from V, D and J gene segments. The immunoglobulin (Ig) heavy chain locus spans 3Mb and undergoes locus contraction to enable recombination between Vh gene segments at the distal end of the locus with DJ segments at the proximal end. To gain a molecular understanding of locus contraction we have characterized the three dimensional (3D) chromatin configuration of the locus. These studies have allowed the identification of specific DNA motifs that may underlie locus contraction. To test this proposition we have knocked out various elements using CRISPR-Cas9 technology in cell lines and mice. Using a combination of non-B cells, Abelson transformed pro-B cell lines and primary pro-B cells we are now defining basic chromatin locus looping as distinct from chromatin interactions responsible for locus-wide contraction. These studies have implication for the architecture of topological domains and sub-domains. These studies are providing insights regarding the mechanism facilitating a fully functional Ig repertoire required for humoral immunity and providing a conceptual framework to understand the influence of SNPs to customize an individual’s humoral response to pathogens.
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Igh class switch recombination (CSR) occurs by a DNA rearrangement which brings one of seven downstream CH genes near the mature V gene replacing C with other CH genes. The recombination event focuses on regions of repetitive sequence upstream of each CH gene, called switch (S), and produces a new hybrid DNA combination with concomitant deletion of the intervening genetic material. Study of genetic rearrangements within Ig genes offers a unique opportunity to understand programmed recombination in eukaryotic cells. We have shown that the 3’ end of the Igh locus undergoes a set of discrete chromatin configurations which facilitate CSR in mature B cells. Our recent studies suggest that these 3D chromatin topologies have a profound effect on the molecular mechanism of CSR.
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Somatic hypermutation (SHM) occurs in germinal center B cells and involves the creation of extremely high frequency mutations focus to V region segments. Selection of V gene mutations in the germinal center reaction leads to emergence of high affinity Ig specific to the tiggering antigen. SHM is required for affinity maturation of the Ig repertoire and for the emergence of high affinity Ab titers. We are studying the mechanism of SHM and how DNA lesions introduced by activation induced deaminase (AID) are converted to mutations, a hallmark feature of SHM. Using CRISPR-Cas9 methods we have identified a new gene that plays a profound role in SHM in mice and are using mice deficient in this gene to probe SHM mechanism.
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PhD, Albert Einstein College of Medicine (Bronx, NY)