David Schatz is interested in understanding the early development of the immune system, particularly the processes that assemble and diversify antigen receptor genes, reactions known as V(D)J recombination and somatic hypermutation.
V(D)J Recombination and Somatic Hypermutation
The B and T lymphocytes that constitute the adaptive immune system make use of highly diverse antigen receptor molecules, known as immunoglobulins (Igs) and T cell receptors, to combat infectious agents. The central interest of the Schatz lab is to understand the two major processes that generate and optimize this diverse repertoire of antigen receptors: V(D)J recombination and somatic hypermutation. We study these reactions using a wide variety of molecular, genetic, cellular, and biochemical approaches. A central focus of our research is understanding how V(D)J recombination and somatic hypermutation are regulated and targeted specifically to antigen receptor genes. We have discovered that the B cell genome is protected from damage as a result of somatic hypermutation by two distinct mechanisms: specific targeting of the mutator AID and gene-specific, high-fidelity DNA repair. More recently, we have found that Ig gene enhancers serve as the key elements that target somatic hypermutation preferentially to Ig genes. We have also demonstrated that the RAG proteins associate with many different sites in the genome, which would appear to increase their threat to genome stability. We are particularly interested in understanding why V(D)J recombination and somatic hypermutation sometimes affect the wrong genes and how such mistakes contribute to the development of B cell lymphomas and leukemias. Finally, we are studying how the proteins encoded by the recombination-activating genes, RAG1 and RAG2, interact with and bend substrate DNA during the DNA cleavage phase of V(D)J recombination. Research in this last area involves protein biochemistry and biophysics, including structural approaches. Other research includes a wide range of techniques involving molecular biology, cell culture, chromatin, and epigenetics. Projects are typically available in some or all of these areas, depending on the availability of mentors.