Alexander Tarakhovsky, M.D., Ph.D.
Encounters with pathogens can alter the function of immune-cell genes in a number of ways 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 their effect on long-lasting immune and non-immune cell responses to the environment.
An organism’s response to environmental stresses has both a predetermined and an adaptive nature. The predetermined response reflects the cell-type specific differences in signaling pathways and gene expression programs, while adaptive responses reflect the ability of individual cells within a given lineage to integrate distinct environmental cues and respond to them in a well-calibrated fashion. Both types of 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, the 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 non-immune cell responses to the environment.
Several years ago, the laboratory proposed the “histone mimicry” paradigm as a novel mechanism for regulation of gene expression. According to this paradigm, the regulation of gene expression could be controlled by histone-like entities present in non-histone proteins that can compete with histones for the regulators of gene expression. The foundation of this model originates from the identification of the histone mimic within the histone methyltransferase G9a, which plays the important role of gene silencing. Further studies demonstrated the presence of histone mimics in a large number of human and mouse proteins. 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, hijacking chromatin-based pathways of the immune response. The histone mimics concept led the Tarakhovsky laboratory to develop synthetic histone mimics that regulate inflammatory gene expression by interfering with the association between histones and transcriptional regulators. In the future, the laboratory plans to extend its research toward the mechanism of epigenetic conditioning of host cells by pathogens. This work may help to elucidate the basis of chronic inflammatory disorders that are initiated by infection but can persist in the absence of infectious agents.