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Professor and Director
Director, Institute of Basic Biomedical Sciences
Molecular Biology and Genetics
733 N. Broadway
Baltimore MD 21205
Mechanisms of Development in the Immune System
The laboratory is interested in molecular and genetic mechanisms responsible for development of the immune system. The generation of immunologic diversity provides a spectacular example of genomic plasticity in the form of V(D)J recombination. This process, which builds antigen receptor genes from discrete gene segments, is a potential source of DNA damage and is subject to tight control. One control mechanism, identified in this laboratory, restricts V(D)J recombination to a specific time in cell cycle through the periodic destruction of the V(D)J recombinase. Using a combination of genetics and biochemistry, we have defined this mechanism and shown that it protects against the development of lymphoid cancers and their associated chromosomal translocations. Many common childhood lymphoid cancers show evidence of aberrant V(D)J recombination, and these events can be modelled in mutant mice that undergo mistimed DNA rearrangements.
The recombination of antigen receptor genes is subject to tight developmental regulation and this is enforced epigenetically through changes in chromatin structure. We are interested understanding how recombination is coupled to chromatin state. Our group has recently defined one such meechanism, which involves the binding of an active chromatin mark, H3K4me3, to the V(D)J recombinase. Engagement of H3K4me3 by the recombinase stimulates DNA cleavage in vitro and is required for efficient recombination in vivo. Strikingly, the H3K4me3 histone modification is in fact an allosteric activator that induces conformational changes within the DNA-binding domains and the catalytic core of the recombinase. Current work is aimed at understanding how epigenetic marks such as H3K4me3 and other structural features interact with the V(D)J recombinase to enforce locus-specific rearrangement.
Another important unsolved set of problems in development surrounds the generation of immune cells from blood-forming stem cells in the bone marrow. While we know a great deal about the transcriptional control networks that support cell fate decisions in the developing immune system, far less is known about the signals that are provided by surrounding cells – the stroma. We have found that hedgehog– a critical morphogenic signal – maintains stromal cells in a state that promotes the generation of immune cells from stem cells. When hedgehog signaling is switched off in stromal cells, their ability to support immune cell differentiation is greatly impaired. Osteoblasts – a type of stromal cell – are critical for the development of antibody-forming cells in the mouse. We have generated mice in which hedgehog signaling is interrupted specifically in the osteoblast lineage. In these animals the generation of antibody-forming cells from stem cells is profoundly impaired. By understanding how hedgehog signaling in stromal cells promotes immune development we hope to be better able to manipulate human immune responses for future therapeutic uses.
Bettridge, J., Ward, A., Na, C.-H., Pandey, A., Desiderio, S. (2017) H3K4me3 induces allosteric conformational changes in the DNA-binding and catalytic regions of the V(D)J recombinase. Proc. Natl. Acad. Sci. 114: 1904-1909.
Lu C., Ward A., Bettridge J., Liu Y., Desiderio S. (2015) An autoregulatory mechanism imposes allosteric control on the V(D)J recombinase by histone H3 methylation. Cell Rep. Jan 6;10(1):29-38.
Cooper CL, Hardy RR, Reth M, Desiderio S. (2012) Non-cell-autonomous hedgehog signaling promotes murine B lymphopoiesis from hematopoietic progenitors. Blood 119: 5438-48.
Zhang, L., Reynolds, T.L., Shan, X. and Desiderio, S. (2011) Coupling of V(D)J recombination to the cell cycle suppresses genomic instability and lymphoid tumorigenesis. Immunity 34: 163-174.
Liu Y, Subrahmanyam R, Chakraborty T, Sen R, Desiderio S. (2007) A plant homeodomain in RAG-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement. Immunity 27:561-71.
Caraveo, G., van Rossum, D.B., Patterson, R.L., Snyder, S.H. and Desiderio, S. (2006) Action of TFII-I outside the nucleus as an inhibitor of agonist-induced calcium entry. Science. 314:122-5.
Jiang, H., Chang, F.-C., Ross, A.E., Lee, J., Nakayama, K., Nakayama, K. and Desiderio, S. (2005) Ubiquitylation of RAG-2 by SKP2-SCF links destruction of the V(D)J recombinase to the cell cycle. Molecular Cell. 18: 699-709.
Ross, A.E., Vuica, M. and Desiderio, S. (2003) Overlapping signals for protein degradation and nuclear localization define a role for intrinsic RAG-2 nuclear uptake in dividing cells. Mol. Cell. Biol. 23:5308-5319.
Yoo, J.-Y., Huso, D.L., Nathans, D. and Desiderio, S. (2002) Specific ablation of Stat3в distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock. Cell. 108:331-344.