Understanding how normal cells become tumorigenic and elucidating the details of the molecular mechanisms underlying this transition is key to our overall understanding of human cancer. Recent work has shown that epigenetic regulation of chromatin plays a central role in transcription, and it is becoming clear that modification of chromatin by BRG1/hBRM-based hSWI/SNF complexes and histone-modifying enzymes such as protein arginine methyltransferase 5 (PRMT5) is involved in the control of cell growth and proliferation. Currently, little is known about the role played by these chromatin-modifying enzymes in human lymphoid malignancies including mantle cell lymphoma (MCL), which remains a fatal disease. Research in MCL has focused on expression analysis of a select number of genes, and to date only very few genes have been identified. We have recently shown that BRG1 and hBRM-associated PRMT5 methylates histone H3 arginine 8 (H3R8) as well as H4R3, and that increased expression of PRMT5 induces transformation by inhibiting transcription of suppressor of tumorigenecity 7 (ST7) and non-metastatic 23-H1 (NM23-H1) tumor suppressor genes. The hypothesis of this project is that PRMTS-mediated symmetric methylation of H3R8 and H4R3 in the promoter region of tumor suppressor genes is involved in the etiology of cancer. The major goal of this application is to define the mechanisms by which hSWI/SNF-associated PRMT5 regulates gene expression and controls cell proliferation. Based on our findings, which show that PRMT5 levels are increased in transformed lymphoid cells including patient-derived MCL cell lines as well as MCL clinical samples, we plan to investigate in specific Aim 1 the molecular mechanisms involved in regulating PRMT5 gene expression.
In specific Aim 2, we propose to study the mechanism by which PRMT5 induces transcriptional repression, and to examine whether there is an inverse relationship between PRMT5 and its target genes in a larger cohort of MCL clinical samples. To enhance our understanding of how hSWI/SNF-associated PRMT5 contributes to the pathogenesis of MCL, experiments in Aim 2 will also focus on using a ChlP-on-Chip platform to delineate the coordinated recruitment of PRMT5 and methylation of H3R8 in normal B cells as well as MCL cells. We have firmly established that S77 and NM23-H1 are direct targets of hSWI/SNF-associated PRMT5. Therefore, experiments in the third Aim will focus on determining whether normalizing ST7 and NM23-H1 expression or knocking down PRMT5 can affect in vivo tumorigenecity of MCL cell lines. These studies will not only allow us to unravel how PRMT5 gene expression becomes aberrant in MCL, but will also allow us to profile PRMTS-mediated epigenetic modification of chromatin that specifies changes in transcriptional performance in MCL cells, and ultimately develop tools to diagnose as well as treat MCL.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Mietz, Judy
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Ohio State University
Schools of Medicine
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Alinari, Lapo; Mahasenan, Kiran V; Yan, Fengting et al. (2015) Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood 125:2530-43
Seth-Vollenweider, Tanya; Joshi, Sneha; Dhawan, Puneet et al. (2014) Novel mechanism of negative regulation of 1,25-dihydroxyvitamin D3-induced 25-hydroxyvitamin D3 24-hydroxylase (Cyp24a1) Transcription: epigenetic modification involving cross-talk between protein-arginine methyltransferase 5 and the SWI/SNF complex. J Biol Chem 289:33958-70
Chung, Jihyun; Karkhanis, Vrajesh; Tae, Sookil et al. (2013) Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing. J Biol Chem 288:35534-47
Karkhanis, Vrajesh; Wang, Li; Tae, Sookil et al. (2012) Protein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase ? catalytic subunit gene, POLD1. J Biol Chem 287:29801-14
Mallappa, Chandrashekara; Hu, Yu-Jie; Shamulailatpam, Priscilla et al. (2011) The expression of myogenic microRNAs indirectly requires protein arginine methyltransferase (Prmt)5 but directly requires Prmt4. Nucleic Acids Res 39:1243-55
Karkhanis, Vrajesh; Hu, Yu-Jie; Baiocchi, Robert A et al. (2011) Versatility of PRMT5-induced methylation in growth control and development. Trends Biochem Sci 36:633-41
Tae, Sookil; Karkhanis, Vrajesh; Velasco, Kevin et al. (2011) Bromodomain protein 7 interacts with PRMT5 and PRC2, and is involved in transcriptional repression of their target genes. Nucleic Acids Res 39:5424-38
Dacwag, Caroline S; Bedford, Mark T; Sif, Saïd et al. (2009) Distinct protein arginine methyltransferases promote ATP-dependent chromatin remodeling function at different stages of skeletal muscle differentiation. Mol Cell Biol 29:1909-21
Wang, Li; Pal, Sharmistha; Sif, Said (2008) Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells. Mol Cell Biol 28:6262-77
Pal, Sharmistha; Sif, Said (2007) Interplay between chromatin remodelers and protein arginine methyltransferases. J Cell Physiol 213:306-15

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