Normal cell growth requires coordinated and regulated gene expression that is associated with changes in chromatin structure. This study focuses on understanding the role of human SWI/SNF (hSWI/SNF) chromatin remodeling complexes and its associated proteins, PRMT5 and mSIN3A/HDAC2, in the control of gene expression and cancer. The findings in this thesis show that hSWI/SNF complexes are involved in transcriptional activation as well as repression and the latter is mediated through associations with repressor proteins, mSIN3/HDAC and PRMT5. Characterization of the methyltransferase activity of PRMT5 revealed that PRMT5 preferentially methylates hypoacetylated histones H3 and H4 at arginine 8 and 3, respectively. When PRMT5 expression was reduced in NIH3T3 cells, 227 genes were upregulated while 43 genes were downregulated indicating a global role for PRMT5 in transcriptional repression. Using chromatin immunoprecipitation assays I have shown that PRMT5 represses tumor suppressor genes, ST7 and NM23, by methylating histones H3R8 and H4R3 at the promoter region. Moreover, overexpression of PRMT5 results in hyperproliferation and anchorage independent growth of NIH3T3 cells, whereas knockdown of PRMT5 decreased cell growth and proliferation of NIH3T3 as well as Raji and JeKo lymphoma cells. I have found that PRMT5 protein expression and global symmetric dimethylation of H3R8 and H4R3 are elevated in mantle cell lymphoma (MCL) cell lines and clinical samples. In stark contrast, steady state PRMT5 mRNA level was low in transformed MCL cells compared to normal B cells, suggesting that PRMT5 mRNA is not efficiently translated in normal B cells. To understand the mechanism underlying the translational inhibition of PRMT5 mRNA, expression of micro-RNAs (miR) that can bind to the 3'UTR of PRMT5 were analyzed. It was found that miR-96 expression was reduced in transformed MCL cells and that miR-96 can inhibit PRMT5 translation both in vitro and in vivo. This study suggests that the hSWI/SNF associated protein, PRMT5 is an oncogene whose overexpression caused partly due to reduced levels of miR-96 is associated with cancer.
|School:||The Ohio State University|
|Department:||Molecular, Cellular, and Developmental Biology|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/09(E), Dissertation Abstracts International|
|Keywords:||H3r8 and h4r3 methylation, Hswi/snf complexes, Mantle cell lymphoma (mcl), Prmt5, St7|
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