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Our research focuses on the epigenetic control of gene expression. Epigenetics is the study of inherited changes in gene expression or cell phenotype that are independent of DNA sequence, but rather, are controlled by modifications to chromatin. The most dramatic example of epigenetic control is the specialization of cells that occurs during embryonic development and adult cell differentiation, whereby the DNA in each cell is largely identical, but specific genes sets are switched on or off. These on-off gene states are “memorized” through many cell divisions. Errors in this process can lead to a variety of diseases, including cancer. “Epigenetic gene silencing” refers to the heritable shut-off of genes. The two major mechanisms that underlie epigenetic silencing are DNA methylation and histone modifications, and hundreds of factors participate in initiating and maintaining these modifications on chromatin. Inappropriate gene silencing can lead to cancer and other diseases, but unlike gene inactivation due to mutations, epigenetic gene silencing is reversible. One goal of our research is to identify networks and novel cellular factors that maintain epigenetic gene silencing, such that new therapies can be devised to reactivate critical genes. Furthermore, as epigenetic mechanisms control cellular identity and plasticity, we are investigating strategies whereby cancer cells can be returned to a normal state.

The projects being carried out in our laboratory address the fundamental roles of epigenetic silencing factors, and their relevance to cancer and other diseases. First, we have developed and implemented a high throughput siRNA screen to functionally probe each cellular factor for its participation in epigenetic processes. Second, we are investigating the roles of epigenetic regulation in the plasticity of cancer cells. Third, as retroviral DNA can be inactivated by the host cell epigenetic silencing machinery, we are using these viruses as robust probes to study the silencing process. Lastly, we are investigating how certain dietary compounds may provide chemopreventive effects by influencing epigenetic events.  

1. Poleshko A, Shalginskhih N, Katz RA. Functional networks of human epigenetic factors. In: Epigenomics: From Chromatin Biology to Therapeutics (Appasani, K., ed.). Cambridge University Press, in press.
2. Poleshko A, Einarson MB, Adams PD, Zhang R, Skalka AM, Katz RA. Identification of a functional network of human epigenetic silencing factors. J. Biol Chem. 2010;285:422-33, Epub 2009 Oct 30. PubMed
3. Frescas D, Guardavaccaro D, Kuchay SM, Kato H, Poleshko A, Basrur V, Elenitoba-Johnson KS, Katz RA, Pagano M. KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state. Cell Cycle. 2008;7:3539-47. PubMed
4. Poleshko A, Palagin I, Zhang R, Boimel P, Castagna C, Adams PD, Skalka AM, Katz RA. Identification of cellular proteins that maintain retroviral epigenetic silencing: evidence for an antiviral response. J Virol. 2008;82:2313-23. PubMed