Thrombospondin-1 Is a Transcriptional Repression Target of PRMT6

Protein arginine methyltransferase 6 (PRMT6) is known to catalyze the generation of asymmetric dimethylarginine in polypeptides. Although the cellular role of PRMT6 is not well understood, it has been implicated in human immunodeficiency virus pathogenesis, DNA repair, and transcriptional regulation. PRMT6 is known to methylate histone H3 Arg-2 (H3R2), and this negatively regulates the lysine methylation of H3K4 resulting in gene repression. To identify in a nonbiased manner genes regulated by PRMT6 expression, we performed a microarray analysis on U2OS osteosarcoma cells transfected with control and PRMT6 small interfering RNAs. We identified thrombospondin-1 (TSP-1), a potent natural inhibitor of angiogenesis, as a transcriptional repression target of PRMT6. Moreover, we show that PRMT6-deficient U2OS cells exhibited cell migration defects that were rescued by blocking the secreted TSP-1 with a neutralizing peptide or blocking α-TSP-1 antibody. PRMT6 associates with the TSP-1 promoter and regulates the balance of methylation of H3R2 and H3K4, such that in PRMT6-deficient cells H3R2 was hypomethylated and H3K4 was trimethylated at the TSP-1 promoter. Using a TSP-1 promoter reporter gene, we further show that PRMT6 directly regulates the TSP-1 promoter activity. These findings show that TSP-1 is a transcriptional repression target of PRMT6 and suggest that neutralizing the activity of PRMT6 could inhibit tumor progression and therefore may be of cancer therapeutic significance. Protein arginine methyltransferase 6 (PRMT6) is known to catalyze the generation of asymmetric dimethylarginine in polypeptides. Although the cellular role of PRMT6 is not well understood, it has been implicated in human immunodeficiency virus pathogenesis, DNA repair, and transcriptional regulation. PRMT6 is known to methylate histone H3 Arg-2 (H3R2), and this negatively regulates the lysine methylation of H3K4 resulting in gene repression. To identify in a nonbiased manner genes regulated by PRMT6 expression, we performed a microarray analysis on U2OS osteosarcoma cells transfected with control and PRMT6 small interfering RNAs. We identified thrombospondin-1 (TSP-1), a potent natural inhibitor of angiogenesis, as a transcriptional repression target of PRMT6. Moreover, we show that PRMT6-deficient U2OS cells exhibited cell migration defects that were rescued by blocking the secreted TSP-1 with a neutralizing peptide or blocking α-TSP-1 antibody. PRMT6 associates with the TSP-1 promoter and regulates the balance of methylation of H3R2 and H3K4, such that in PRMT6-deficient cells H3R2 was hypomethylated and H3K4 was trimethylated at the TSP-1 promoter. Using a TSP-1 promoter reporter gene, we further show that PRMT6 directly regulates the TSP-1 promoter activity. These findings show that TSP-1 is a transcriptional repression target of PRMT6 and suggest that neutralizing the activity of PRMT6 could inhibit tumor progression and therefore may be of cancer therapeutic significance. Protein arginine methyltransferases (PRMTs) 3The abbreviations used are: PRMTprotein arginine methyltransferaseChIPchromatin immunoprecipitationPBSphosphate-buffered salineTSP-1thrombospondin-1WD40 repeat (also known as WD or Β-transducin repeat)tryptophan-aspartic acid (W-D) dipeptide repeatsiRNAsmall interfering RNAHIVhuman immunodeficiency virusGFPgreen fluorescent protein. 3The abbreviations used are: PRMTprotein arginine methyltransferaseChIPchromatin immunoprecipitationPBSphosphate-buffered salineTSP-1thrombospondin-1WD40 repeat (also known as WD or Β-transducin repeat)tryptophan-aspartic acid (W-D) dipeptide repeatsiRNAsmall interfering RNAHIVhuman immunodeficiency virusGFPgreen fluorescent protein. catalyze the addition of one or two methyl groups to the guanidino nitrogen atoms of arginine resulting in asymmetric and symmetric dimethylarginines using S-adenosylmethionine as a methyl donor (1Bedford M.T. Clarke S.G. Mol. Cell. 2009; 33: 1-13Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar, 2Lee Y.H. Stallcup M.R. Mol. Endocrinol. 2009; 23: 425-433Crossref PubMed Scopus (162) Google Scholar). Protein arginine methylation is a common post-translational modification (3Boisvert F.M. Côté J. Boulanger M.C. Richard S. Mol. Cell. Proteomics. 2003; 2: 1319-1330Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar), and it has been shown to regulate many cellular processes, including nuclear export (4Shen E.C. Henry M.F. Weiss V.H. Valentini S.R. Silver P.A. Lee M.S. Genes Dev. 1998; 12: 679-691Crossref PubMed Scopus (250) Google Scholar), protein-protein interactions (5Bedford M.T. Frankel A. Yaffe M.B. Clarke S. Leder P. Richard S. J. Biol. Chem. 2000; 275: 16030-16036Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 6Friesen W.J. Massenet S. Paushkin S. Wyce A. Dreyfuss G. Mol. Cell. 2001; 7: 1111-1117Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar), ribosome biogenesis (7Bachand F. Silver P.A. EMBO J. 2004; 23: 2641-2650Crossref PubMed Scopus (129) Google Scholar, 8Swiercz R. Person M.D. Bedford M.T. Biochem. J. 2005; 386: 85-91Crossref PubMed Scopus (127) Google Scholar), DNA repair (9Boisvert F.M. Déry U. Masson J.Y. Richard S. Genes Dev. 2005; 19: 671-676Crossref PubMed Scopus (160) Google Scholar, 10El-Andaloussi N. Valovka T. Toueille M. Steinacher R. Focke F. Gehrig P. Covic M. Hassa P.O. Schär P. Hübscher U. Hottiger M.O. Mol. Cell. 2006; 22: 51-62Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), genomic stability (11Yu Z. Chen T. Hebert J. Li E. Richard S. Mol. Cell. Biol. 2009; 29: 2982-2996Crossref PubMed Scopus Google Scholar), W.J. Paushkin S. Wyce A. Massenet S. G. J. M. Dreyfuss G. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar, F.M. J. Boulanger M.C. P. F. Richard S. J. Biol. PubMed Scopus Google Scholar, J. A. F. R. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Côté J. S. Bedford M.T. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and gene J. P. 2001; PubMed Scopus Google Scholar, J. Stallcup M.R. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Stallcup M.R. PubMed Scopus Google Scholar, J. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google was identified by to has methylation and methylate that A. N. Lee J. Clarke S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). PRMT6 to methylate in A. N. Lee J. Clarke S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google as in M.C. R. Bedford M.T. Richard S. J. 2005; PubMed Scopus Google and DNA N. Valovka T. Toueille M. Steinacher R. Focke F. Gehrig P. Covic M. Hassa P.O. Schär P. Hübscher U. Hottiger M.O. Mol. Cell. 2006; 22: 51-62Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). analysis has that PRMT6 a methylation of a arginine Frankel A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). PRMT6 is nuclear A. N. Lee J. Clarke S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), is not well of to methylate and PRMT6 is implicated in by as a M.C. R. Bedford M.T. Richard S. J. 2005; PubMed Scopus Google Scholar, Richard S. J. PubMed Scopus Google Scholar, Frankel M. Richard S. PubMed Scopus Google Scholar, Richard S. 2006; PubMed Scopus Google Scholar). PRMT6 has been shown to methylate the in the and regulates R. Clarke S. Biochem. 2005; PubMed Scopus Google Scholar, Clarke S. PubMed Scopus Google Scholar). that PRMT6 DNA a role in DNA repair N. Valovka T. Toueille M. Steinacher R. Focke F. Gehrig P. Covic M. Hassa P.O. Schär P. Hübscher U. Hottiger M.O. Mol. Cell. 2006; 22: 51-62Abstract Full Text Full Text PDF PubMed Scopus (131) Google is well known that histone methylation gene T. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). it was shown that asymmetric of histone H3 Arg-2 with the protein-protein interactions of A. M. M. J. T. PubMed Scopus Google Scholar, M. S. F.M. M. Cell. Full Text Full Text PDF PubMed Scopus Google and the repeat with H3K4 E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of in promoter the of the lysine H3K4 the of and is A. M. M. J. T. PubMed Scopus Google Scholar, E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it was shown that PRMT6 is the of H3R2 E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These findings suggest that PRMT6 is a of gene the of a microarray was used to identify genes regulated by PRMT6. We that thrombospondin-1 is in PRMT6-deficient TSP-1 is a of P. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). TSP-1 is by many cell and secreted the J. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, PubMed Scopus Google Scholar, J. 7: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). TSP-1 is a potent natural inhibitor of and cell migration R. J. Biol. PubMed Scopus Google Scholar, J. Mol. PubMed Scopus Google Scholar). TSP-1 cell migration by cell including with repeat S. E. Biochem. PubMed Scopus (162) Google Scholar, M. J. J. Biol. PubMed Scopus Google Scholar). TSP-1 gene is regulated by P. P. J. Biol. Chem. Full Text PDF PubMed Google and N. PubMed Scopus Google Scholar). been and the TSP-1 gene is regulated by DNA methylation A. S. Y.H. J. PubMed Scopus Google Scholar). is is the histone of the TSP-1 this we show that a of genes and and genes and in PRMT6-deficient U2OS of the genes was is therefore a repression target of PRMT6. methylation of the H3R2 was as the by TSP-1 gene was of TSP-1 this we identified a genes in and cellular migration regulated by PRMT6. by of PRMT6 in U2OS cells to the of genes that were and genes that were by using of the genes that is by PRMT6 is the secreted a potent inhibitor of and cell We show that PRMT6-deficient U2OS cells exhibited cell migration defects that were rescued by blocking the secreted TSP-1 with a neutralizing peptide or blocking α-TSP-1 PRMT6 was with the TSP-1 promoter and regulated the balance of methylation of H3R2 and H3K4, such that in PRMT6-deficient cells H3R2 was hypomethylated and H3K4 was trimethylated at the TSP-1 promoter with gene Using a TSP-1 promoter reporter gene, we further show that PRMT6 directly regulates the TSP-1 promoter. These findings show that TSP-1 is a transcriptional repression target of PRMT6 and that of H3R2 regulate TSP-1 methylation and not been shown to regulate cell and been identified as of using (3Boisvert F.M. Côté J. Boulanger M.C. Richard S. Mol. Cell. Proteomics. 2003; 2: 1319-1330Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, G. S. Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar). These findings suggest that arginine methylation is to a role in protein-protein interactions cell the was shown to be by and this regulates with and M. N. S. S. S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the role of or in cell migration a role of in or cell migration is by the of as a J. J. J. Clarke S. Bedford M.T. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). findings show that the nuclear PRMT6 cell migration by including in cellular of the H3R2 is with gene repression and with gene E. F. F. M. PubMed Scopus Google Scholar). of H3R2 with with A. M. M. J. T. PubMed Scopus Google Scholar, M. S. F.M. M. Cell. Full Text Full Text PDF PubMed Scopus Google and E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google such that in the lysine methyltransferase is not to promoter that the of PRMT6 be to and the genes that in U2OS PRMT6-deficient cells genes that by PRMT6 is that the by may be as in A. M. M. J. T. PubMed Scopus Google Scholar). and regulated genes genes known to be regulated by H3K4 E. F. F. M. PubMed Scopus Google Scholar, T. T. S. T. R. G. A. E. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and be in PRMT6 We not identify in microarray analysis that genes in U2OS and that the of PRMT6 not further the H3R2 that is hypomethylated in genes that in the PRMT6-deficient cells a of regulated genes by PRMT6 and suggest that PRMT6 may as a genes or methyl that the of H3R2 in the of DNA A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). DNA was to M. M. R. J. 2001; PubMed Scopus Google Scholar), and gene T. M. E. T. P. F. M.R. N. F. A. Côté J. 2006; PubMed Scopus Google Scholar). has been that cells TSP-1 to defects in cellular migration Z. M. J. M. Li A. P. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). by to TSP-1 gene is We not identify in microarray analysis with findings that PRMT6 was to A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google is known to be regulated by P. P. J. Biol. Chem. Full Text PDF PubMed Google Scholar), N. PubMed Scopus Google Scholar), as well as DNA methylation A. S. Y.H. J. PubMed Scopus Google Scholar), and we this to histone arginine modification by PRMT6. show that blocking secreted TSP-1 cell migration in PRMT6-deficient U2OS a of genes was identified in the cellular migration in microarray analysis of PRMT6-deficient that the genes may to the of PRMT6-deficient show that PRMT6 regulates cell migration and by in the TSP-1 promoter. findings suggest that PRMT6 may be to cancer cell and Protein arginine methyltransferases (PRMTs) 3The abbreviations used are: PRMTprotein arginine methyltransferaseChIPchromatin immunoprecipitationPBSphosphate-buffered salineTSP-1thrombospondin-1WD40 repeat (also known as WD or Β-transducin repeat)tryptophan-aspartic acid (W-D) dipeptide repeatsiRNAsmall interfering RNAHIVhuman immunodeficiency virusGFPgreen fluorescent protein. 3The abbreviations used are: PRMTprotein arginine methyltransferaseChIPchromatin immunoprecipitationPBSphosphate-buffered salineTSP-1thrombospondin-1WD40 repeat (also known as WD or Β-transducin repeat)tryptophan-aspartic acid (W-D) dipeptide repeatsiRNAsmall interfering RNAHIVhuman immunodeficiency virusGFPgreen fluorescent protein. catalyze the addition of one or two methyl groups to the guanidino nitrogen atoms of arginine resulting in asymmetric and symmetric dimethylarginines using S-adenosylmethionine as a methyl donor (1Bedford M.T. Clarke S.G. Mol. Cell. 2009; 33: 1-13Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar, 2Lee Y.H. Stallcup M.R. Mol. Endocrinol. 2009; 23: 425-433Crossref PubMed Scopus (162) Google Scholar). Protein arginine methylation is a common post-translational modification (3Boisvert F.M. Côté J. Boulanger M.C. Richard S. Mol. Cell. Proteomics. 2003; 2: 1319-1330Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar), and it has been shown to regulate many cellular processes, including nuclear export (4Shen E.C. Henry M.F. Weiss V.H. Valentini S.R. Silver P.A. Lee M.S. Genes Dev. 1998; 12: 679-691Crossref PubMed Scopus (250) Google Scholar), protein-protein interactions (5Bedford M.T. Frankel A. Yaffe M.B. Clarke S. Leder P. Richard S. J. Biol. Chem. 2000; 275: 16030-16036Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 6Friesen W.J. Massenet S. Paushkin S. Wyce A. Dreyfuss G. Mol. Cell. 2001; 7: 1111-1117Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar), ribosome biogenesis (7Bachand F. Silver P.A. EMBO J. 2004; 23: 2641-2650Crossref PubMed Scopus (129) Google Scholar, 8Swiercz R. Person M.D. Bedford M.T. Biochem. J. 2005; 386: 85-91Crossref PubMed Scopus (127) Google Scholar), DNA repair (9Boisvert F.M. Déry U. Masson J.Y. Richard S. Genes Dev. 2005; 19: 671-676Crossref PubMed Scopus (160) Google Scholar, 10El-Andaloussi N. Valovka T. Toueille M. Steinacher R. Focke F. Gehrig P. Covic M. Hassa P.O. Schär P. Hübscher U. Hottiger M.O. Mol. Cell. 2006; 22: 51-62Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar), genomic stability (11Yu Z. Chen T. Hebert J. Li E. Richard S. Mol. Cell. Biol. 2009; 29: 2982-2996Crossref PubMed Scopus Google Scholar), W.J. Paushkin S. Wyce A. Massenet S. G. J. M. Dreyfuss G. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar, F.M. J. Boulanger M.C. P. F. Richard S. J. Biol. PubMed Scopus Google Scholar, J. A. F. R. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, Côté J. S. Bedford M.T. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and gene J. P. 2001; PubMed Scopus Google Scholar, J. Stallcup M.R. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Stallcup M.R. PubMed Scopus Google Scholar, J. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). arginine methyltransferase thrombospondin-1 acid (W-D) dipeptide repeat small interfering human immunodeficiency virus fluorescent protein. arginine methyltransferase thrombospondin-1 acid (W-D) dipeptide repeat small interfering human immunodeficiency virus fluorescent protein. PRMT6 was identified by to has methylation and methylate that A. N. Lee J. Clarke S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). PRMT6 to methylate in A. N. Lee J. Clarke S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google as in M.C. R. Bedford M.T. Richard S. J. 2005; PubMed Scopus Google and DNA N. Valovka T. Toueille M. Steinacher R. Focke F. Gehrig P. Covic M. Hassa P.O. Schär P. Hübscher U. Hottiger M.O. Mol. Cell. 2006; 22: 51-62Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). analysis has that PRMT6 a methylation of a arginine Frankel A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). PRMT6 is nuclear A. N. Lee J. Clarke S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), is not well of to methylate and PRMT6 is implicated in by as a M.C. R. Bedford M.T. Richard S. J. 2005; PubMed Scopus Google Scholar, Richard S. J. PubMed Scopus Google Scholar, Frankel M. Richard S. PubMed Scopus Google Scholar, Richard S. 2006; PubMed Scopus Google Scholar). PRMT6 has been shown to methylate the in the and regulates R. Clarke S. Biochem. 2005; PubMed Scopus Google Scholar, Clarke S. PubMed Scopus Google Scholar). that PRMT6 DNA a role in DNA repair N. Valovka T. Toueille M. Steinacher R. Focke F. Gehrig P. Covic M. Hassa P.O. Schär P. Hübscher U. Hottiger M.O. Mol. Cell. 2006; 22: 51-62Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). is well known that histone methylation gene T. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). it was shown that asymmetric of histone H3 Arg-2 with the protein-protein interactions of A. M. M. J. T. PubMed Scopus Google Scholar, M. S. F.M. M. Cell. Full Text Full Text PDF PubMed Scopus Google and the repeat with H3K4 E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of in promoter the of the lysine H3K4 the of and is A. M. M. J. T. PubMed Scopus Google Scholar, E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it was shown that PRMT6 is the of H3R2 E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These findings suggest that PRMT6 is a of gene the of To a microarray was used to identify genes regulated by PRMT6. We that thrombospondin-1 is in PRMT6-deficient TSP-1 is a of P. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). TSP-1 is by many cell and secreted the J. Biol. PubMed Scopus Google Scholar, J. Biol. Chem. Full Text PDF PubMed Google Scholar, PubMed Scopus Google Scholar, J. 7: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). TSP-1 is a potent natural inhibitor of and cell migration R. J. Biol. PubMed Scopus Google Scholar, J. Mol. PubMed Scopus Google Scholar). TSP-1 cell migration by cell including with repeat S. E. Biochem. PubMed Scopus (162) Google Scholar, M. J. J. Biol. PubMed Scopus Google Scholar). TSP-1 gene is regulated by P. P. J. Biol. Chem. Full Text PDF PubMed Google and N. PubMed Scopus Google Scholar). been and the TSP-1 gene is regulated by DNA methylation A. S. Y.H. J. PubMed Scopus Google Scholar). is is the histone of the TSP-1 this we show that a of genes and and genes and in PRMT6-deficient U2OS of the genes was is therefore a repression target of PRMT6. methylation of the H3R2 was as the by TSP-1 gene was of TSP-1 regulation. this we identified a genes in and cellular migration regulated by PRMT6. by of PRMT6 in U2OS cells to the of genes that were and genes that were by using of the genes that is by PRMT6 is the secreted a potent inhibitor of and cell We show that PRMT6-deficient U2OS cells exhibited cell migration defects that were rescued by blocking the secreted TSP-1 with a neutralizing peptide or blocking α-TSP-1 PRMT6 was with the TSP-1 promoter and regulated the balance of methylation of H3R2 and H3K4, such that in PRMT6-deficient cells H3R2 was hypomethylated and H3K4 was trimethylated at the TSP-1 promoter with gene Using a TSP-1 promoter reporter gene, we further show that PRMT6 directly regulates the TSP-1 promoter. These findings show that TSP-1 is a transcriptional repression target of PRMT6 and that of H3R2 regulate TSP-1 methylation and not been shown to regulate cell and been identified as of using (3Boisvert F.M. Côté J. Boulanger M.C. Richard S. Mol. Cell. Proteomics. 2003; 2: 1319-1330Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, G. S. Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar). These findings suggest that arginine methylation is to a role in protein-protein interactions cell the was shown to be by and this regulates with and M. N. S. S. S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the role of or in cell migration a role of in or cell migration is by the of as a J. J. J. Clarke S. Bedford M.T. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). findings show that the nuclear PRMT6 cell migration by including in cellular of the H3R2 is with gene repression and with gene E. F. F. M. PubMed Scopus Google Scholar). of H3R2 with with A. M. M. J. T. PubMed Scopus Google Scholar, M. S. F.M. M. Cell. Full Text Full Text PDF PubMed Scopus Google and E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google such that in the lysine methyltransferase is not to promoter that the of PRMT6 be to and the genes that in U2OS PRMT6-deficient cells genes that by PRMT6 is that the by may be as in A. M. M. J. T. PubMed Scopus Google Scholar). and regulated genes genes known to be regulated by H3K4 E. F. F. M. PubMed Scopus Google Scholar, T. T. S. T. R. G. A. E. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and be in PRMT6 We not identify in microarray analysis that genes in U2OS and that the of PRMT6 not further the H3R2 that is hypomethylated in genes that in the PRMT6-deficient cells a of regulated genes by PRMT6 and suggest that PRMT6 may as a genes or methyl that the of H3R2 in the of DNA A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). DNA was to M. M. R. J. 2001; PubMed Scopus Google Scholar), and gene T. M. E. T. P. F. M.R. N. F. A. Côté J. 2006; PubMed Scopus Google Scholar). has been that cells TSP-1 to defects in cellular migration Z. M. J. M. Li A. P. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). by to TSP-1 gene is We not identify in microarray analysis with findings that PRMT6 was to A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google is known to be regulated by P. P. J. Biol. Chem. Full Text PDF PubMed Google Scholar), N. PubMed Scopus Google Scholar), as well as DNA methylation A. S. Y.H. J. PubMed Scopus Google Scholar), and we this to histone arginine modification by PRMT6. show that blocking secreted TSP-1 cell migration in PRMT6-deficient U2OS a of genes was identified in the cellular migration in microarray analysis of PRMT6-deficient that the genes may to the of PRMT6-deficient show that PRMT6 regulates cell migration and by in the TSP-1 promoter. findings suggest that PRMT6 may be to cancer cell and this we identified a genes in and cellular migration regulated by PRMT6. by of PRMT6 in U2OS cells to the of genes that were and genes that were by using of the genes that is by PRMT6 is the secreted a potent inhibitor of and cell We show that PRMT6-deficient U2OS cells exhibited cell migration defects that were rescued by blocking the secreted TSP-1 with a neutralizing peptide or blocking α-TSP-1 PRMT6 was with the TSP-1 promoter and regulated the balance of methylation of H3R2 and H3K4, such that in PRMT6-deficient cells H3R2 was hypomethylated and H3K4 was trimethylated at the TSP-1 promoter with gene Using a TSP-1 promoter reporter gene, we further show that PRMT6 directly regulates the TSP-1 promoter. These findings show that TSP-1 is a transcriptional repression target of PRMT6 and that of H3R2 regulate TSP-1 methylation and not been shown to regulate cell and been identified as of using (3Boisvert F.M. Côté J. Boulanger M.C. Richard S. Mol. Cell. Proteomics. 2003; 2: 1319-1330Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar, G. S. Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar). These findings suggest that arginine methylation is to a role in protein-protein interactions cell the was shown to be by and this regulates with and M. N. S. S. S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the role of or in cell migration a role of in or cell migration is by the of as a J. J. J. Clarke S. Bedford M.T. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). findings show that the nuclear PRMT6 cell migration by including in cellular of the H3R2 is with gene repression and with gene E. F. F. M. PubMed Scopus Google Scholar). of H3R2 with with A. M. M. J. T. PubMed Scopus Google Scholar, M. S. F.M. M. Cell. Full Text Full Text PDF PubMed Scopus Google and E. F. F. M. PubMed Scopus Google Scholar, E. A. J. Genes Dev. PubMed Scopus Google Scholar, A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google such that in the lysine methyltransferase is not to promoter that the of PRMT6 be to and the genes that in U2OS PRMT6-deficient cells genes that by PRMT6 is that the by may be as in A. M. M. J. T. PubMed Scopus Google Scholar). and regulated genes genes known to be regulated by H3K4 E. F. F. M. PubMed Scopus Google Scholar, T. T. S. T. R. G. A. E. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), and be in PRMT6 We not identify in microarray analysis that genes in U2OS and that the of PRMT6 not further the H3R2 that is hypomethylated in genes that in the PRMT6-deficient cells a of regulated genes by PRMT6 and suggest that PRMT6 may as a genes or methyl We that the of H3R2 in the of DNA A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). DNA was to M. M. R. J. 2001; PubMed Scopus Google Scholar), and gene T. M. E. T. P. F. M.R. N. F. A. Côté J. 2006; PubMed Scopus Google Scholar). has been that cells TSP-1 to defects in cellular migration Z. M. J. M. Li A. P. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). by to TSP-1 gene is We not identify in microarray analysis with findings that PRMT6 was to A. J. Richard S. Bedford M.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). TSP-1 is known to be regulated by P. P. J. Biol. Chem. Full Text PDF PubMed Google Scholar), N. PubMed Scopus Google Scholar), as well as DNA methylation A. S. Y.H. J. PubMed Scopus Google Scholar), and we this to histone arginine modification by PRMT6. show that blocking secreted TSP-1 cell migration in PRMT6-deficient U2OS a of genes was identified in the cellular migration in microarray analysis of PRMT6-deficient that the genes may to the of PRMT6-deficient show that PRMT6 regulates cell migration and by in the TSP-1 promoter. findings suggest that PRMT6 may be to cancer cell and We with the microarray with with

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