Research

Research Overview

The main focus of our research is to investigate how the misregulation of epigenetic mechanisms results in aberrant gene expression and tumorigenesis. Epigenetic controls of gene expression consist of DNA sequence-independent changes in chromatin structure that include DNA methylation, histone modifications, and microRNAs. While altered patterns of DNA methylation have been tightly linked to cancer through the suppression of tumor suppressor genes, the relationship between alterations in histone modifications and the pathogenesis of cancer is significantly less understood. Histone modifications function by facilitating direct effects on chromatin structure and through the recruitment of chromatin-associated factors, or “reader proteins” that translate histone marks into specific biological outcomes. A key question that remains is how alterations in the maintenance and interpretation of histone marks influence various chromatin states and thereby contribute to human cancer? To address this question we are focused on investigating how misregulated histone modifications affect the regulation of gene expression by the tumor suppressor protein p53. p53 functions as a transcription factor to regulate the expression of a wide array of genes that, in turn, facilitate diverse cellular responses that include cell cycle arrest and apoptosis. Striking the perfect balance in the activation of the various p53-response pathways is essential for preventing the propagation of cells that harbor DNA mutations and can lead to tumor development.

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By employing in vitro biochemical transcription systems reconstituted with purified factors and recombinant chromatin templates, we are able to identify precise and direct (causal) functions of histone modifications and transcriptional effector proteins at the chromatin level. Our in vitro assays provide a powerful and unique means to identify regulatory mechanisms that function both independently and cooperatively at the epigenetic level to mediate coordinated and conversely, aberrant transcriptional control. Our biochemical assays combined with proteomic/genomic, cell-based assays, and genetic analyses will provide a greater mechanistic understanding of epigenetic alterations in the deregulation of gene expression in oncogenesis, and will ultimately advance the potential for target based screening approaches, an issue of great significance in light of the recent successes in targeting histone modification effector proteins/readers for developing cancer therapies.

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