Brg1 and hBrm-associated Histone Methyltransferase:Target Genes in Cancer Therap

Ohio State University, Columbus OH

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Abstract

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