Heads of Laboratories
Professor
Laboratory of Lymphocyte Signaling
Alexander.Tarakhovsky@rockefeller.edu
The interaction of immune cells with their environment leads to changes in the function of genes that contribute to effective immune response. These changes in gene expression are controlled by various signaling pathways, including those that converge at the chromatin level. The environment-induced changes in chromatin are responsible for the formation of immune and non-immune cell phenotypes that may persist for significant periods of time. The Tarakhovsky lab studies the mechanisms by which pathogens affect the function of chromatin, and how they affect long-lasting immune and non-immune cell responses to the environment.
The current focus of the Tarakhovsky laboratory is on the mechanism of epigenetic control of immune cell function. Several years ago, the lab found that Polycomb protein Ezh2 has an essential role in immunoglobulin gene rearrangement in B cells. This finding was the first proof of histone methyltransferase’s importance in transcription-unrelated specialized somatic cell function. Further extension of these studies revealed an interconnected web of cytosolic and chromatin-related events that control normal cell differentiation and responses. The Tarakhovsky lab discovered a previously unknown role of Polycomb protein Ezh2 in cytosolic signaling, which Ezh2 contributes directly to T cell antigen receptor mediated T cell activation. Protein lysine methylation being a part of cell signaling machinery raised an intriguing possibility of the common principles that govern the assembly of protein complexes in chromatin and cell cytosol, or at the cell membrane. In support of this model, the lab found that numerous non-histone proteins in mammalian cells possess histone-like sequences (histone mimics). Furthermore, the laboratory found that pathogenic microorganisms carry “histone mimics” in the proteins that critically contribute to pathogen-mediated suppression of the host immune response. This finding led them to propose a mechanism, according to which histone mimics in bacterial and viral proteins may serve as histone surrogates, thus competing with the host epigenome for the proteins that “read” information embedded in posttranslationally modified histones. The histone mimics concept led the Tarakhovsky lab to the idea of developing synthetic histone mimics that regulate gene expression by interfering with the histone “readers.” Along these lines, the lab has found that synthetic antagonists of certain histone readers can effectively control the expression of key inflammatory genes. In the future, the laboratory plans to extend its research toward an understanding of the mechanism of epigenetic conditioning of host cells by pathogens. This research may help to understand the basis of chronic inflammatory disorders that are initiated by infection but can persist in the absence of infectious agents.
CAREER
Dr. Tarakhovsky received his medical degree from the Kiev Medical Institute in Ukraine in 1978 and his Ph.D. from the Institute
for Oncology at the Academy of Science in Kiev in 1982. He has worked as a research associate at the Institute for Oncology, the
All-Union Cancer Research Center in Moscow and the Institute for Molecular Genetics in Tallinn, Estonia. In 1990 he joined as a
postdoc the Institute of Genetics at the University of Cologne; he was promoted to group leader in 1993 and tenured professor and
head of the Laboratory of Lymphocyte Signaling in 1995. He moved that lab to Rockefeller in 2000, when he was appointed Irene
Diamond Associate Professor. He was named full professor in 2003.
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