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1 pp. DNA DNA DNA DNA DNA unfinished symphony DNA -CpG- CpG Disease and epigenome analysis Minoru Toyota, Hiromu Suzuki, and Masahiro Kai Department of Biochemistry, Sapporo Medical University, South-, West-, Chuo-ku, Sapporo -, Japan DNA DNA DNMT DNMT A DNMT B DNA X Alu LINE N K H K H K H K CpG CpG DNA DNA DNA

2 WNT Ras p WNT WNT SFRP DKK DNA Ras RASSF DNA p p p DNA ES H K H K bivalent H K H K H K DNA

3 DNA DNA bisulfite DNA DNA p CDKN A p CDKN B DNA CHFR CHFR G M CHFR DNA DNA O -methylguanine-dna methyltransferase MGMT MGMT K-ras G A hmlh hmlh APC WNT WNT WNT APC β- WNT SFRP DKK DNA

4 APC β- TCF β- SFRP SFRP SFRP WNT Ras Ras RAF Ras K-ras BRAF Ras Ras Ras RASSF IGFBP DNA K-ras BRAF RASSF RASSF IGFBP DNA K-ras BRAF p p mir- b c DNA DNMT DNMT B DKO microrna TaqMan PCR mir- b c DKO mir- b c mir- b c CDK MET mir- b c p MET CDK - - σ p ARF p DNA p p p B GALNT DNA B GALNT Sd a Sd a sle x B GALNT DNA B GALNT Sd a LINE bisulfite-pyrosequencing DNA DNMT B DNA CpG island methylator phenotype CIMP CIMP hmlh CIMP BRAF Agouti Agouti DNA Kamei Dnmt a DNA CpG MeCP Rett DNA Mill

5 DNA DNA ES ES H K H K bivalent H K H K bivalent DNA ips ips ips ipc bivalent H K DNA ips ipc DNA Issa DNA DNA Maekita Helicobactor pylori B B DNA S - DNA DNA Kaneto p CDKN A B C p CDKN A p CDKN A EBV EBV EBV DNMT DNMT DNA bisulfite-pcr DNA DNA ER H. pylori H. pylori DNA DNA DNA B C p CDKN A EBV Agouti DNA

6 DNA DNA bisulfite DNA PCR COBRA combined bisulfite restriction analysis COBRA pyrosequence COBRA bisulfite DNA PCR DNA DNA TaqMan PCR methylight mass array CpG methylated CpG island amplification MCA MCA PCR DNA DNA MCA representational difference analysis RDA MCA MCA HRK p DFNA MCA BAC CpG BAC MCA nuclear receptor L CRABP MD Anderson Issa MCA BAC CpG MCA microarray MCAM MCAM bisulfite-pcr MCAM Weber DNA DNA BAC DNA methylated DNA immunoprecipitation MeDIP CpG DNA Weber chromatin immunoprecipitation, ChIP ChIP DNA DNA- DNA PCR ChIP DNA ChIP on ChIP DNA DNA

7 ChIP on ChIP ChIP H K HCT DNMT DNMT B DKO ChIP on ChIP ChIP H KSFRP DKO ChIP DNA PCR CpG MBD DNA bisulfite DNA Lister ES DNA bisulfite ES CpG CpG ES DNA DNA H K SOLiD ChIP ChIP on ChIP H K DNA DNMT DNMT B DKO DNA H K DNMT H K K bivalent DNA ChIP DNA

8 Qiu, J. Nature,,. Herman, J.G., Jen, J., Merlo, A., & Baylin, S.B. Cancer Res.,,. Herman, J.G., Merlo, A., Mao, L., Lapidus, R.G., Issa, J.P., Davidson, N.E., Sidransky, D., & Baylin, S.B. Cancer Res.,,. Ogi, K., Toyota, M., Mita, H., Satoh, A., Kashima, L., Sasaki, Y., Suzuki, H., Akino, K., Nishikawa, N., Noguchi, M., Shinomura, Y., Imai, K., Hiratsuka, H., & Tokino, T. Cancer Biol. Ther.,,. Satoh, A., Toyota, M., Itoh, F., Sasaki, Y., Suzuki, H., Ogi, K., Kikuchi, T., Mita, H., Yamashita, T., Kojima, T., Kusano, M., Fujita, M., Hosokawa, M., Endo, T., Tokino, T., & Imai, K. Cancer Res.,,. Toyota, M., Sasaki, Y., Satoh, A., Ogi, K., Kikuchi, T., Suzuki, H., Mita, H., Tanaka, N., Itoh, F., Issa, J.P., Jair, K.W., Schuebel, K.E., Imai, K., & Tokino, T. Proc. Natl. Acad. Sci. USA.,,. Toyota, M., Suzuki, H., Yamashita, T., Hirata, K., Imai, K., Tokino, T., & Shinomura, Y. Cancer Sci.,,. Esteller, M., Toyota, M., Sanchez-Cespedes, M., Capella, G., Peinado, M.A., Watkins, D.N., Issa, J.P., Sidransky, D., Baylin, S.B.,&Herman,J.G. Cancer Res.,,. Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J.G., Baylin, S.B., & Issa, J.P. Proc. Natl. Acad. Sci. U S A.,,. Sato, H., Suzuki, H., Toyota, M., Nojima, M., Maruyama, R., Sasaki, S., Takagi, H., Sogabe, Y., Sasaki, Y., Idogawa, M., Sonoda, T., Mori, M., Imai, K., Tokino, T., & Shinomura, Y. Carcinogenesis,,. Suzuki, H., Watkins, D.N., Jair, K.W., Schuebel, K.E., Markowitz, S.D., Chen, W.D., Pretlow, T.P., Yang, B., Akiyama, Y., Van Engeland, M., Toyota, M., Tokino, T., Hinoda, Y., Imai, K., Herman, J.G., & Baylin, S.B. Nat. Genet.,,. Akino, K., Toyota, M., Suzuki, H., Mita, H., Sasaki, Y., Ohe- Toyota, M., Issa, J.P., Hinoda, Y., Imai, K., & Tokino, T. Gastroenterology,,. Suzuki, H., Igarashi, S., Nojima, M., Maruyama, R., Yamamoto, E., Kai, M., Akashi, H., Watanabe, Y., Yamamoto, H.,Sasaki,Y.,Itoh,F.,Imai,K.,Sugai,T.,Shen,L.,Issa,J.P., Shinomura, Y., Tokino, T., & Toyota, M. Carcinogenesis,,. Toyota, M., Suzuki, H., Sasaki, Y., Maruyama, R., Imai, K., Shinomura, Y., & Tokino, T. Cancer Res.,,. Esteller, M., Tortola, S., Toyota, M., Capella, G., Peinado, M. A., Baylin, S.B., & Herman, J.G. Cancer Res.,,. Suzuki, H., Itoh, F., Toyota, M., Kikuchi, T., Kakiuchi, H., & Imai, K. Cancer Res.,,. Kawamura, Y.I., Toyota, M., Kawashima, R., Hagiwara, T., Suzuki, H., Imai, K., Shinomura, Y., Tokino, T., Kannagi, R., & Dohi, T. Gastroenterology,,. Yamamoto, E., Toyota, M., Suzuki, H., Kondo, Y., Sanomura, T., Murayama, Y., Ohe-Toyota, M., Maruyama, R., Nojima, M., Ashida, M., Fujii, K., Sasaki, Y., Hayashi, N., Mori, M., Imai, K., Tokino, T., & Shinomura, Y. Cancer Epidemiol. Biomarkers Prev.,,. Bestor, T.H. Hum. Mol. Genet.,,. Shen, L., Toyota, M., Kondo, Y., Lin, E., Zhang, L., Guo, Y., Hernandez, N.S., Chen, X., Ahmed, S., Konishi, K., Hamilton, S.R., & Issa, J.P. Proc. Natl. Acad. Sci. U S A.,,. Weisenberger, D.J., Siegmund, K.D., Campan, M., Young, J., Long, T.I., Faasse, M.A., Kang, G.H., Widschwendter, M., Weener, D., Buchanan, D., Koh, H., Simms, L., Barker, M., Leggett, B., Levine, J., Kim, M., French, A.J., Thibodeau, S.N., Jass, J., Haile, R., & Laird, P.W. Nat. Genet.,,. Wolff, G.L., Kodell, R.L., Moore, S.R., & Cooney, C.A. FASEB J.,,. Kamei, Y., Suganami, T., Ehara, T., Kanai, S., Hayashi, K., Yamamoto, Y., Miura, S., Ezaki, O., Okano, M., & Ogawa, Y. Obesity Silver Spring,,. Chahrour, M. & Zoghbi, H.Y. Neuron,,. Mill, J., Tang, T., Kaminsky, Z., Khare, T., Yazdanpanah, S., Bouchard, L., Jia, P., Assadzadeh, A., Flanagan, J., Schumacher, A., Wang, S.C., & Petronis, A. Am.J.Hum. Genet.,,. Bernstein, B.E., Mikkelsen, T.S., Xie, X., Kamal, M., Huebert, D.J., Cuff, J., Fry, B., Meissner, A., Wernig, M., Plath, K., Jaenisch, R., Wagschal, A., Feil, R., Schreiber, S.L., & Lander, E.S. Cell,,. Ohm, J.E., McGarvey, K.M., Yu, X., Cheng, L., Schuebel, K. E., Cope, L., Mohammad, H.P., Chen, W., Daniel, V.C., Yu, W., Berman, D.M., Jenuwein, T., Pruitt, K., Sharkis, S.J., Watkins, D.N., Herman, J.G., & Baylin, S.B. Nat. Genet.,,. Schlesinger, Y., Straussman, R., Keshet, I., Farkash, S., Hecht, M., Zimmerman, J., Eden, E., Yakhini, Z., Ben-Shushan, E., Reubinoff, B.E., Bergman, Y., Simon, I., & Cedar, H. Nat. Genet.,,. Widschwendter, M., Fiegl, H., Egle, D., Mueller-Holzner, E., Spizzo, G., Marth, C., Weisenberger, D.J., Campan, M., Young, J., Jacobs, I., & Laird, P.W. Nat. Genet.,,. Miyoshi, N., Ishii, H., Nagai, K., Hoshino, H., Mimori, K., Tanaka, F., Nagano, H., Sekimoto, M., Doki, Y., & Mori, M. Proc. Natl. Acad. Sci. U S A.,,. Issa, J.P., Ottaviano, Y.L., Celano, P., Hamilton, S.R., Davidson, N.E., & Baylin, S.B. Nat. Genet.,,.

9 Issa, J.P., Ahuja, N., Toyota, M., Bronner, M.P., & Brentnall, T.A. Cancer Res.,,. Maekita, T., Nakazawa, K., Mihara, M., Nakajima, T., Yanaoka, K., Iguchi, M., Arii, K., Kaneda, A., Tsukamoto, T., Tatematsu, M., Tamura, G., Saito, D., Sugimura, T., Ichinose, M., & Ushijima, T. Clin. Cancer Res.,,. Lin, R.K., Hsieh, Y.S., Lin, P., Hsu, H.S., Chen, C.Y., Tang, Y.A., Lee, C.F., & Wang, Y.C. J. Clin. Invest.,,. Kaneto, H., Sasaki, S., Yamamoto, H., Itoh, F., Toyota, M., Suzuki, H., Ozeki, I., Iwata, N., Ohmura, T., Satoh, T., Karino, Y., Toyota, J., Satoh, M., Endo, T., Omata, M., & Imai, K. Gut,,. Kusano, M., Toyota, M., Suzuki, H., Akino, K., Aoki, F., Fujita, M., Hosokawa, M., Shinomura, Y., Imai, K., & Tokino, T. Cancer,,. Toyota, M., Ho, C., Ahuja, N., Jair, K.W., Li, Q., Ohe-Toyota, M., Baylin, S.B., & Issa, J.P. Cancer Res.,,. Akino, K., Toyota, M., Suzuki, H., Imai, T., Maruyama, R., Kusano, M., Nishikawa, N., Watanabe, Y., Sasaki, Y., Abe, T., Yamamoto, E., Tarasawa, I., Sonoda, T., Mori, M., Imai, K., Shinomura, Y., & Tokino, T. Cancer Sci.,,. Obata, T., Toyota, M., Satoh, A., Sasaki, Y., Ogi, K., Akino, K., Suzuki, H., Murai, M., Kikuchi, T., Mita, H., Itoh, F., Issa, J.P., Tokino, T., & Imai, K. Clin. Cancer Res.,,. Misawa, A., Inoue, J., Sugino, Y., Hosoi, H., Sugimoto, T., Hosoda, F., Ohki, M., Imoto, I., & Inazawa, J. Cancer Res.,,. Tanaka, K., Imoto, I., Inoue, J., Kozaki, K., Tsuda, H., Shimada, Y., Aiko, S., Yoshizumi, Y., Iwai, T., Kawano, T., & Inazawa, J. Oncogene,,. Estecio, M.R., Yan, P.S., Ibrahim, A.E., Tellez, C.S., Shen, L., Huang, T.H., & Issa, J.P. Genome Res.,,. Weber, M., Davies, J.J., Wittig, D., Oakeley, E.J., Haase, M., Lam, W.L., & Schubeler, D. Nat. Genet.,,. Ballestar, E., Paz, M.F., Valle, L., Wei, S., Fraga, M.F., Espada, J., Cigudosa, J.C., Huang, T.H., & Esteller, M. EMBO J.,,. Serre, D., Lee, B.H., & Ting, A.H. Nucleic Acids Res.,,. Lister, R., Pelizzola, M., Dowen, R.H., Hawkins, R.D., Hon, G., Tonti-Filippini, J., Nery, J.R., Lee, L., Ye, Z., Ngo, Q.M., Edsall, L., Antosiewicz-Bourget, J., Stewart, R., Ruotti, V., Millar, A.H., Thomson, J.A., Ren, B., & Ecker, J.R. Nature,,.

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<4D F736F F D F4997B995F18D908F915F8DA188E45F81408DCF82DD> S 終了 -1 平成 18 年度科学研究費補助金 ( 基盤研究 (S)) 研究終了報告書記入に当たっては平成 18 年度科学研究費補助金 ( 基盤研究 (S)) 研究終了報告書記入要領を参照してくださいローマ字 IMAI KOUZO 1 研究代表者氏名今井浩三 2 所属研究機関部局職札幌医科大学学長 3 研究課題名和文遺伝子不安定性ならびにメチル化異常による消化器癌の発生とその分子標的治療