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Heads of Laboratories

Head shot of Alexander Tarakhovsky
Alexander Tarakhovsky, M.D., Ph.D.
Professor
Laboratory of Immune Cell Epigenetics and Signaling
Alexander.Tarakhovsky@rockefeller.edu

Encounters with pathogens can alter the function of immune cell genes through a number of means, including alterations to chromatin, the complex formed by DNA and its packaging proteins. The resulting changes in gene expression can produce persistent traits. The Tarakhovsky lab studies the mechanisms by which pathogens affect chromatin function and how they affect long-lasting immune and nonimmune cell responses to the environment.

Organism response to environmental stresses has both a predetermined, as well as an adaptive, nature. The predetermined response reflects the cell type-specific differences in signaling pathways and gene expression programs. In turn, adaptive responses reflect the ability of individual cells within a given lineage to integrate distinct environmental cues and to respond to them in a well-calibrated fashion. The predetermined and adaptive responses depend largely on tightly controlled gene expression programs that operate within limits imposed by a gene-specific chromatin environment. In the immune system, changes in chromatin are associated with, and contribute to, differentiation of hematopoietic stem cells into highly diverse immune cell subpopulations. Cell type-specific programs that drive responses of differentiated immune cells to pathogens differ significantly between B and T lineage cells as well as between cells of the adaptive and innate immune systems. The Tarakhovsky laboratory studies the mechanisms by which pathogens affect the function of chromatin, as well as how they affect long-lasting immune and nonimmune cell responses to the environment.

Several years ago, the Tarakhovsky laboratory proposed the “histone mimicry” paradigm as a novel mechanism for regulation of gene expression. According to this paradigm, regulation of gene expression could be controlled by histone-like entities present in nonhistone proteins that can compete with histones for the regulators of gene expression. The foundation of this model originates from identification of the histone mimic within the histone methyltransferase G9a, which plays the important role of gene silencing. Further studies show the presence of histone mimics in a large number of human and mouse proteins. 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 hijacking chromatin-based pathways of immune response. The histone mimics concept led the Tarakhovsky laboratory to develop synthetic histone mimics that regulate inflammatory gene expression by interfering with association between histones and transcription regulators. 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 elucidate the basis of chronic inflammatory disorders that are initiated by infection but can persist in the absence of infectious agents.


EDUCATION

M.D., 1978
Kiev Medical Institute

Ph.D., 1982
Institute for Oncology, Academy of Science, Kiev

POSTDOC

University of Cologne, 1990–1992

POSITIONS

Research Associate, 1992–1994
Group Leader, 1994–1996
Professor, 1996–2000
Institute for Genetics, University of Cologne

Associate Professor, 2000–2003
Professor, 2003–
The Rockefeller University

SELECTED PUBLICATIONS

Marazzi, I. et al. Suppression of the antiviral response by an influenza histone mimic. Nature 483, 428–433 (2012).

Fang, T.C. et al. Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J. Exp. Med. 209, 661–669 (2012).

Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).

Sampath, S.C. et al. Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol. Cell 27, 596–608 (2007).

Su, I.H. et al. Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell 121, 425–436 (2005).


Dr. Tarakhovsky is a faculty member in the David Rockefeller Graduate Program and the Tri-Institutional M.D.-Ph.D. Program.