Histone Modification and Changes in Chromatin: Silencing of Tumor Suppressor Gene

Ohio State University, Columbus OH

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Abstract

The genomic DNA of eukaryotes must be highly compacted for packaging within the nuclei of cells. This[unreadable] compaction is achieved through the formation of a complex nucleoprotein structure known as chromatin.[unreadable] Chromatin is a highly dynamic structure that exerts a powerful influence over cellular processes that involve[unreadable] accessing chromosomal DNA. The primary protein components of chromatin are the core histones H2A,[unreadable] H2B, H3 and H4. The post-translational modification of the core histones is an important mechanism by[unreadable] which chromatin structure is regulated. The core histones have been shown to undergo several types of[unreadable] modification such as acetylation, methylation, phosphorylation, ubiquitination and ADP-ribosylation. In[unreadable] addition, these modifications are often found at multiple sites in the core histones. The main focus of our[unreadable] current proposal is to use the sensitive technique of mass spectrometry as a foundation for the[unreadable] comprehensive identification, mapping and characterization of histone post-translational modifications.[unreadable] Our initial aim in these studies is to use mass spectrometry to analyze core histones isolated from bovine[unreadable] thymus. This will allow for the identification and mapping of the complete spectrum of histone posttranslational[unreadable] modifications present in higher eukaryotic chromatin. As novel sites of modification are[unreadable] identified, the characterization of their in vivo function will be done in yeast, taking advantage of the unique[unreadable] ability to genetically manipulate the core histones in this organism.[unreadable] Many observations point to the critical role that the proper regulation of chromatin structure plays in[unreadable] preventing the uncontrolled cell growth characteristic of cancer. Therefore, we propose experiments that[unreadable] seek to identify characteristic alterations in the extent or pattern of histone modifications that correlate with[unreadable] Chronic Lymphocytic Leukemia.[unreadable] As described in other sections of this program project, the modification of chromatin structure is being[unreadable] explored as a potential chemotherapeutic strategy. Small molecule inhibitors of histone deacetylases have[unreadable] shown potential in controlling the growth and differentiation of cancer cells. To most effectively utilize these[unreadable] compounds, it is vital to more precisely characterize the alterations in histone modifications that are induced[unreadable] by these drugs. Therefore, we propose to use mass spectrometry to comprehensively characterize the[unreadable] changes in histone modification that result from the treatment of leukemia cells with chemotherapeutic agents[unreadable] that target chromatin structure.[unreadable]