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Department of Biomedical Sciences

 

 

 
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Sebastian D. Fugmann

Sebastian D. Fugmann

Position

Professor

Education

Ph.D., University of Ulm, Germany

E-mail

sdfugmann@mail.cgu.edu.tw

Office Tel

+886-3-211-8800 ext.3478

Fax

+886-3-211-8700

Laboratory

Laboratory of Molecular Immunology

Spciality

Molecular Immunology, DNA recombination and repair

Lab & Research Interest

All multicellular organisms are constantly challenged by a plethora of potentially lethal pathogens and thus require protection to survive. These defense mechanisms can be broadly divided into the "innate" and the "adaptive" immune systems. The former relies on the recognition of conserved pathogen associated molecular patterns where as the latter utilizes randomly generated antigen receptors, immunoglobulins (Igs) and T cell receptors (TCRs), without pre-defined specificities. The central theme of my laboratory is to understand the molecular mechanisms of programmed gene rearrangements and mutagenesis that generate the diverse antigen receptor repertoires essential for adaptive immunity.

Until now five such gene diversification processes have been reported: V(D)J recombination, class switch recombination (CSR), somatic hypermutation (SHM), immunoglobulin gene conversions (GCV), and the recently discovered assembly of the variable lymphocyte receptors in the jawless vertebrates, lamprey and hagfish. While V(D)J recombination occurs in the Ig and TCR loci of B and T lymphocyte progenitors, CSR, SHM, and GCV are initiated after the encounter of antigen and are restricted to the Ig genes of B lymphocytes. All five processes are unique as they involve the violation of a central dogma, the life-long maintenance of genomic DNA, to efficiently combat potentially deleterious pathogens that are encountered on a daily basis.

Our current work is focused on two specific questions:

1) The evolution of V(D)J recombination and adaptive immunity.

We recently identified a gene pair in the genome of the purple sea urchin (Strongylocentrotus purpuratus) with striking similarity to the vertebrate recombination activating genes 1 and 2 (RAG1 and RAG2 genes. The genes were previously thought to be unique to jawed vertebrates as the sole function of RAG1 and RAG2 is to mediate V(D)J recombination which does not occur in invertebrates. We are currently pursuing in vitro and in vivo studies to characterize their molecular function, their role in sea urchin development and immunity, and the relationship to the classical vertebrate RAG1/2 proteins. We are also studying the sea urchin immune system in general, as it likely represents a transition between the classic invertebrate innate immunity defined in flies and the more advanced immune system of jawed vertebrates.

2) The targeting of SHM and GCV to Ig gene loci.

SHM and GCV are mutagenic processes that are recruited specifically to Ig genes where they exert their beneficial function increasing the affinity of the encoded antibody. As they could be potentially very dangerous when acting on non-Ig genes, there are mechanisms in place to ensure their tight targeting to the correct chromosomal region. We recently discovered mutation enhancer elements (MEEs), a novel class of cis-regulatory elements regulating local genomic stability, as mediators of this targeting. We are currently characterizing these elements to understand their mode of action. We are also trying to identify such elements in mammalian Ig gene loci.

Publications

Publications:

  1. Sen, R., Fugmann, S.D. (2012)  Transcription, splicing, and release: are we there yet?. Cell 150:241-3.
  2. Kothapalli, N.K., Fugmann, S.D. (2011)  Targeting of AID-mediated sequence diversification to immunoglobulin genes. Curr. Opin. Immunol. 23:184-9.
  3. Kothapalli, N.R., Collura, K.M., Norton, D.D., Fugmann, S.D. (2011)  Separation of mutational and transcriptional enhancers in Ig genes. J. Immunol. 187:3247-55.
  4. Kothapalli, N.R., Norton, D.D., Fugmann, S.D. (2011)  Classical Mus musculus Igκ enhancers support transcription but not high level somatic hypermutation from a V-lambda promoter in chicken DT40 cells. PLoS One 6:e18955.
  5. Fugmann, S.D. (2010)  The origins of the Rag genes - from transposition to V(D)J recombination.  Semin. Immunol. 22:10-16.
  6. Litman, G., Rast, J.P., Fugmann, S.D(2010)  The origins of vertebrate immune systems.  Nat. Rev. Immunol. 10:533-43.
  7. Delker, R.K., Fugmann, S.D., Papavasiliou, F.N. (2009)  A coming of age story: Activation-induced cytidine deaminase turns 10.  Nat. Immunol. 10:1147-1153.
  8. Kothapalli, N., Norton, D.D., Fugmann, S.D. (2008)  Cutting Edge: A cis-acting DNA element targets AID-mediated sequence diversification to the chicken Ig light chain gene locus.  J. Immunol. 180:2019-23.
  9. Wilson, D., Norton, D.D., Fugmann, S.D. (2008) The PHD domain of the sea urchin RAG2 homolog, SpRAG2L, recognizes dimethylated lysine 4 in histone H3 tails.  Dev. Comp. Immunol. 32:1221-30.
  10. Hibino, T., Loza-Coll, M., Messier, C., Majeske, A.J., Cohen, A.H., Terwilliger, D.P., Buckley, K.M., Brockton, V., Nair, S.V., Berney, K., Fugmann, S.D., Anderson, M.K., Pancer, Z., Cameron, R.A., Smith, L.C., Rast, J.P. (2006)  The immune gene repertoire encoded in the purple sea urchin genome.  Dev Biol. 300:349-65.
  11. Fugmann, S.D., Messier, C., Novack, L.A., Cameron, R.A., Rast, J.P. (2005)  An ancient evolutionary origin of the RAG1/2 gene locus.  Proc. Natl Acad. Sci. USA 103:3728-33.