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Chromatin
Pathways in Development and Oncogenesis |
In eukaryotic cells, DNA is tightly associated with histones as well as non-histone proteins to form the chromatin fiber. Specifically, histones are assembled as octamers composed of two copies of each core histone, H2A, H2B, H3 and H4 in order to form the nucleosome. Histones are subjected to specific modifications that modulate the ionic strength of interactions among the components of the chromatin fiber and dictate the recruitment of additional factors. These specific modifications result in higher order chromatin structure and thereby define the level of accessibility to the DNA strand. Therefore higher order chromatin structure virtually impacts all biological processes related to DNA, including gene expression and genomic stability, both of which are at the nexus of the transformation process. The research in our laboratory is focused on histone modifications, and specifically reversible histone acetylation, as they relate to normal and pathological development in mammals. More specifically, we study how disruption of the normal histone deacetylation pathway affects mammalian development in the mouse, and influence oncogenesis. Several studies suggested that blocking the enzymatic activity of HDAC complexes (e.g., using histone deacetylase inhibitors) could prevent tumorigenesis and selectively induce cell death in transformed cells. While HDACs are integral components of several gene regulatory complexes, HDAC inhibitors developed to date exhibit little or no specificity towards individual HDAC-containing complex. Thus, the identification of pathways involved in the modulation of the activities of specific HDAC complexes is a priority in cancer therapy. Knowledge of these control mechanisms in both normal physiology and malignancy is essential for the better understanding of the malignant process that will allow development of novel therapeutic and diagnostic approaches to human disease. |
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York University School of MedicineDepartment of Pharmacology 550 First Avenue, New York, NY 10016 212-263-7111 © 2000 New York University Contact the Webmaster Ethics and Disclaimer |
