Laboratory of Lymphocyte Biology
Dr. Papavasiliou studies the ways in which cells and organisms diversify and expand the information encoded in their genomes. This can be accomplished through mutation and recombination of DNA, or through changes to RNA that effectively reprogram gene expression, strategies employed by both the immune system and the pathogens seeking to thwart it. Her work has revealed extraordinary plasticity within biological systems.
Using a combination of biochemistry and genetics, Dr. Papavasiliou is studying the molecular basis of the specific type of DNA mutation that underlies the diversification of antibodies in the B lymphocytes of the immune system. When B cells, specialized cells that produce antibodies against foreign molecules, encounter an antigen, mutations are introduced in the genes of their B cell receptors that recognize that antigen. This hypermutation process helps some of those B cells to acquire a higher affinity for the antigen, and those cells are then selected for survival. Without somatic hypermutation, an individual may become immunocompromised.
Hypermutation in B cells is dependent on a protein called activation-induced cytidine deaminase (AID). When AID is expressed in these cells, it changes cytidine residues in the DNA to uracil, which is then recognized as DNA damage. Normally, the cell repairs uracil lesions by properly converting them back to cytidine; somehow, in B cells, the damaged antibody genes are misrepaired, such that the uracil lesion is converted to thymidine. How AID targets antibody genes for deamination and why uracil lesions in antibody genes are misrepaired only in this context are questions under investigation in the Papavasiliou lab.
B cells use DNA mutation to diversify and expand their antibody repertoire, which they need to block entry and eventually remove pathogens. Other organisms use DNA recombination to diversify their surface receptors and specifically evade antibody recognition. For instance, surface antigen variation in parasites like the African trypanosome (Trypanosoma brucei, the causative agent of sleeping sickness) is generated by gene conversion between silent cassettes and one active expression site. Understanding the mechanism that initiates targeted gene conversion in these parasites is an active area of interest in the lab (and an ongoing collaboration with Rockefeller’s George A.M. Cross).
AID belongs to the AID/APOBEC family of cytidine deaminase enzymes, most of which deaminate DNA to initiate mutation. One of these, however, the APOBEC-1 deaminase, functions as an RNA “editor.” Using transcriptome-wide binary comparisons between a genomic DNA sequence and the sequence of its RNA transcript, the Papavasiliou lab has uncovered multiple instances of APOBEC-1 editing that resulted in C-to-U changes in the edited transcript (noted as C-to-T differences between genomic DNA and messenger RNA), which effectively reprogram gene expression. The lab is keenly interested in further understanding the functional relevance of these changes at the organismal level.
Finally, these genome/transcriptome comparisons have revealed a multitude of RNA/DNA alterations that occur at high frequency but cannot be attributed to cytidine deamination. These occur both in coding regions and in regulatory regions, and the lab is currently devising methods to first catalog these and to then characterize them functionally.
B.A. in biology, 1992
The Rockefeller University
Yale University, 1998–2001
Assistant Professor, 2001–2007
Associate Professor, 2007–2016
Adjunct Professor, 2017–
The Rockefeller University
Keck Fellow, 2002
Searle Scholar, 2003
Sinsheimer Fund Scholar, 2005
Thorbecke Award, Society for Leukocyte Biology, 2006
National Institutes of Health Director’s Transformative Research Project Award, 2011
Mugnier, M.R. et al. The in vivo dynamics of antigenic variation in Trypanosoma brucei. Science 347, 1470–1473 (2015).
Fritz, E.L. et al. A comprehensive analysis of the effects of the deaminase AID on the transcriptome and methylome of activated
B cells. Nat. Immunol. 14, 749–755 (2013).
Delker, R.K. et al. Solubility-based genetic screen identifies RING finger protein 126 as an E3 ligase for activation-induced cytidine deaminase. Proc. Natl. Acad. Sci. U.S.A. 110, 1029–1034 (2013).
Rosenberg, B.R. et al. Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3' UTRs. Nat. Struct. Mol. Biol. 18, 230–236 (2011).
Boothroyd, C.E. et al. A yeast-endonuclease-generated DNA break induces antigenic switching in Trypanosoma brucei. Nature 459, 278–281 (2009).