Normal cell growth relies on the maintenance of a balance between activator and represser proteins. Alteration of this balance by either overexpression of a proto-oncogene or inactivation of a tumor suppressor gene can lead to tumorigenesis. Recent studies have unraveled the role played by epigenetic regulation of chromatin in the control of gene transcription, and it is becoming clear that modification of nucleosomes by BRG1/hBRM-based hSWI/SNF complexes and histone modifying enzymes including protein arginine methyltransferase (PRMT5), is involved in the control of cell growth and proliferation. Currently, little is known about genes regulated by the BRG1 and hBRM-associated PRMT5, and the mechanisms used to target its activity to specific regions of chromatin. The major goal of this application is to characterize the BRG1 and hBRM-associated PRMT5 histone methyltransferase activity, identify its target genes, and study the effects of chromatin remodeling and histone arginine methylation on gene expression. Based on our preliminary data, we hypothesize that methylation of histones H3 and H4 in the promoter region of tumor suppressor genes by the BRG1 and hBRM-associated PRMT5 is involved in the etiology of cancer. The experiments proposed in the first two aims will further characterize the interaction of PRMT5 with BRG1 and hBRM-based human SWI/SNF complexes, determine whether chromatin remodeling is required for nucleosomal histone methylation, and examine whether H3 and H4 methylation by PRMT5 changes during the course of the cell cycle. These studies will provide us with clues on the activity and substrate specificity of PRMT5.
The third aim will focus on identifying genes regulated by PRMTS-containing BRG1 and hBRM complexes using both chromatin immunoprecipitation (ChIP) and microarray analyses. These experiments will help us identify direct targets of PRMTS-containing BRG1 and hBRM complexes. In light of our recent findings, the fourth aim will focus on characterizing the chromatin structure and transcription profile of suppressor of tumorigenecity 7 (ST7) and non-metastatic 23 (NM23). Both anti-cancer genes have been identified by microarray analysis and shown to be direct targets of BRG1 and hBRM-associated PRMT5. These studies will provide us with information about the role played by histone arginine methylation in regulating transcription of tumor suppressor genes, and help us understand how the interplay between histone methylation and ATP-dependent chromatin remodeling affects cell growth and proliferation.
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