Faculty Summaries
Richard A. Katz
Richard A. Katz, PhD
Research Professor
  • Adjunct Professor,
    Fels Institute for Cancer Research and Molecular Biology,
    Temple University School of Medicine, Philadelphia, PA
Richard.Katz@fccc.edu
Lab Phone: 215-728-3668
Fax: 215-728-2778
Office: R422
  • Identification of epigenetic silencing factor networks
    Andrey Poleshko & Natalia Shalginskikh, in collaboration with Margret Einarson, Ann Skalka & Yan Zhou

    A genome-wide, gene-by-gene siRNA-based knockdown screen has been developed to identify novel factors and networks that maintain epigenetic gene silencing in human cells. A human reporter cell system was devised whereby reactivation of an epigenetically silent green fluorescent protein (GFP) gene provides a high throughput readout. Screens using the pre-selected and genome-wide siRNA sets have revealed that knockdown of individual factors is sufficient for reactivation, and that specific networks can be identified. These screens have the potential to identify novel cellular pathways that mark chromatin for epigenetic silencing, and thus reveal new targets for epigenetic therapy of cancer and other diseases. Recent studies have focused on the detailed characterization of several novel epigenetic silencing factors identified through this method.

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  • Role of the nuclear lamina in epigenetic control
    Andrey Poleshko, Caroline Burlingame, Katelyn Mansfield, Kelly Dunlevy, Laurie-Ann Davis & Neil Shah, in collaboration with Mark Andrake

    The nuclear lamina is a protein meshwork found under the inner nuclear membrane of metazoan cells. Defects in the nuclear lamina are associated with a variety of diseases, including cancer. One function of the nuclear lamina is to organize heterochromatin at the inner nuclear periphery. However, very little is known about how heterochromatin attaches to the nuclear lamina. Our siRNA-based epigenetic screening approach has identified a previously unstudied human protein that functions to tether heterochromatin to the nuclear lamina. Furthermore, this protein assembles in stepwise manner at mitotic exit, suggesting that it may guide the reattachment of heterochromatin. We are using a variety of methods to further elucidate the detailed mechanisms of heterochromatin-lamina interactions.
     

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  • Epigenetic plasticity of cancer cells
    Yuval Peretz & Shayan Patel, in collaboration with Hong Wu, Alfonso Bellacosa & Jonathan Chernoff

    A prominent feature of tumors, and melanomas in particular, is phenotypic and functional heterogeneity.  We have developed a robust system to study melanoma cell plasticity in culture, whereby genes that drive this process can be identified.  The biological relevance of these factors can then be assessed in human melanoma tissues. This study has identified candidate factors that are drivers of cancer cell plasticity, and therefore may serve as novel targets for therapy, or as biomarkers.  A factor that was identified using this approach was found to be expressed in melanoma tissues.

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  • Epigenetic silencing as an antiviral response
    Natalia Shalginskikh, Andrey Poleshko & Rushaniya Fazliyeva, in collaboration with Ann Skalka & Siddharth Balachandran

    Integrated retroviral DNA is subject to epigenetic silencing in human cells. We previously showed that the human Daxx protein is an antiviral factor that binds to the incoming retroviral DNA-protein complex, and acts as an adapter to recruit epigenetic silencing factors. We recently showed that knockdown of Daxx prior to infection abrogates viral silencing, albeit transiently. We also determined that DNA methylation of retroviral DNA occurs within several days post infection, suggesting that this modification is important for initiating silencing. We also found that Daxx can recruit repressive DNA methyltransferases (DNMTs) to viral DNA, and that knockdown of Daxx resulted in loss of viral DNA methylation and concomitant reactivation of silent viral DNA. These results have important implications for how human cells can respond to foreign viral DNA.

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  • Dietary compounds that influence epigenetic events
    Caroline Burlingame

    Over the past two decades, therapeutic compounds have been developed that promote reactivation of epigenetically silent tumor suppressor genes and selectively kill, or drive differentiation of cancer cells. More recently, compounds that affect epigenetic processes have been isolated as Bioactive Food Components (BFCs). In some cases, these compounds mimic known epigenetic drugs. The presence of these BFCs in specific diets may underlie their cancer preventative properties, and also provide the basis for development of new therapeutics. To identify the epigenetic activities of BFCs, we have used our cell-based system in which an epigenetically silent GFP reporter gene is reactivated in response to epigenetic drug treatment. We are applying this system to characterize known BFC compounds and to identify new phytochemicals that reactivate epigenetically silent genes.

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