Prof. Dr. Alexander Tarakhovsky

Research Area: Epigenetic Impact of Pathogenic Viruses

Website: Tarakhovsky Lab

1. Research Background:

The existence of the highly diverse and frequently pathogenic viruses relies on the extraordinary viruses’ ability to exploit their hosts for the benefit of viral replication and immune system evasion. These viral features evolve constantly in response to the pressure from the host that, in turn, advances its strategies of antiviral resistance in response to viral changes. We are interested in understating of the mechanisms that allow viruses to gain an advance on the host by interfering with the short-term as well as long-term epigenetic processes. 

We have discovered a new phenomenon of viral mimicry of the host epigenetic regulators and show that this mimicry can benefit the virus infection. The overall aim of our research group is to unravel the fundamental regulatory principles of how viruses can interfere with the cell epigenome and identify the role of the virus-epigenome interaction in viral infection and diseases, including age-associated neurodegeneration, caused by the viruses. While we strive to promote the basic research, we are also keen to use our knowledge for the advancement of novel antiviral approaches.

2. Research questions addresses by the group:

We found that many of the viral proteins accumulate in the nucleus as well as nucleolus of the infected cells. We also show that nuclear/nucleolar viral proteins carry distinct structural motifs that are homologous to key regulatory motifs in histones as well as other epigenetic regulators. Our goal is to identify the mechanism of viral proteins interaction with the infected cell chromatin. We also plan to investigate whether viral impact on the chromatin can facilitate the virus-mediated hijacking of the host proteins for the purpose of viral replication and suppression of   the antiviral response. One of our key questions deals with the phenomenon of the long-lasting and possibly transgenerational effects of virus-chromatin interaction. We argue that even transient virus-mediated impact on the chromatin may leave an epigenetic imprint followed by changes in the cell physiology and potentially promote recurring infection, especially at the older age. These questions can be extended further to address the possible role of viruses in “conditioning” human and animal epigenome for the benefit of the viral infection beyond the life of the infected cell or individual. In all our projects we will work with lab-adapted RNA and DNA viruses that faithfully reproduce key features of the pathogenic counterparts. Our studies will use modern methods of virology, chromatin biology, structural studies and computational biology.

3. Possible projects:

  1. Define the role of “histone mimicry” in virus impact on chromatin and infection
  2. Identify the mechanism of the viral nuclear protein’s interaction with nucleosome and their role in nuclear organization and gene function
  3. Address the role of virus interaction with the host nucleolus during virus infection and virus-induced pathogenesis.
  4. Investigate the possible antiviral potential of pharmacological modifiers of virus-epigenome interaction

4. Applied Methods and model organisms:

  • In vitro cultured cell lines, mouse ES cells, ex vivo isolated mouse cells
  • Chromatin studies, e.g. ChIP sequencing, ATAC seq.
  • Large-scale gene analysis at the population and single cell resolution
  • Ribosome profiling
  • Virology assays

5. Desirable skills and qualifications:

Molecular biology, biochemistry and genetics

6. References:

  1. Su I-H, Dobenecker M, Oser M, Basavaraj A, Margueron R, Viale A, Reinberg D, Wulfing C, Tarakhovsky A. Polycomb group protein Ezh2 controls actin polymerization and cell signaling. Cell. 2005; 121:425-36. PMID: 15882624
  2. Sampath SC, Marazzi I, Yap KL, Sampath SC, Krutchinsky AN, Mecklenbräuker I, Viale A, Rudensky E, Zhou MM, Chait BT, Tarakhovsky A. Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol Cell. 2007; 27(4):596-608.  PMID: 17707231 
  3. Marazzi, I, Ho J, Kim J, Manicassamy B, Dewell S, Albrecht RA, Prinjha RK, Jeffrey KL, Lee K, Garcia-Sastre A, Roeder R, Tarakhovsky A. Suppression of the antiviral response by an influenza “histone mimic”. Nature. 2012 Mar 14;483(7390):428-33. PMCID: PMC3598589
  4. Schaefer U, Ho JS, Prinjha RK, Tarakhovsky A.  The "Histone Mimicry" by Pathogens.  Cold Spring Harb Symp Quant Biol. 2014 Apr 28. [PMID: 24733380;  PMCID PMC5406129
  5. Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A., Suppression of inflammation by a synthetic histone mimic. Nature. 2010; Dec 23;468(7327):119-23. PMID: 21068722; PMCID PMCID PMC5415086
  6. Mourão D, Chen S, Schaefer U, Bozzacco L, Carneiro LA, Gerber A, Adura C, Dill BD, Molina H, Carroll T, Paul M, Bhanu NV, Garcia BA, Joberty G, Rioja I, Prinjha RK, Roeder RG, Rice CM, MacDonald MR, Patel D, Tarakhovsky A. A histone-like motif in yellow fever virus contributes to viral replication. bioRxiv. 2020 May 6. doi: