Genome-wide analysis of genomic impinting in cancer

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 14026029
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tottori Univeisity
• Principal Investigator: OSHIMURA Mitsuo Graduate School of Medical Science, Professor, 大学院医学系研究科, 教授 (20111619)
• Co-Investigator(Kenkyū-buntansha): KUGOH Hiroyuki Graduate School of Medical Science, Associate Professor, 大学院医学系研究科, 助教授 (40225131) ; KATOH Motonobu Graduate School of Medical Science, Reaearch Asistant, 大学院医学系研究科, 寄附講座教員 (00273904)
• Project Period (FY): 2002 – 2004
• Keywords: cancer / genomic imprinting / DMR / epjgenetics / chromatin / FISH / LIT1 / IGF2

Research Abstract

It is well known that a variety of genetic and epigenetic changes influence the development and progression of cancer. To understand the interaction of the functional role of imprinted genes for cancers, we investigated 1) isolation of novel imprinted genes, 2) functional analysis of LIT1 imprinted gene and 3) analysis of imprinted genes in some malignant cells, including glioma, esophageal and colorectal cancers.
1) We have identified 143 loci of differential methylated region DMR in human. In addiotion, we isolated 2 novel imprinted gens that exhibit paternal and maternal allele-specific expression using human monochromosomal hybrids. Furthermore, we found that GOI (gain of imprinting) of these imrpinted genes were observed in several glioma cell lines. This result suggests that downregulation of the imprinted genes may be important in the development of glioma.
2) The imprinted noncoding RNA LIT1, a product of the KCNQ1OT1, is involved in cis-limited silencing within an imprinted cluster on human chromosome Ilpl5.5. Although the locus serves as an imprinting center (IC), the function of the LIT1 gene product is unclear. RNA in situ hybridization provides evidence suggesting that the LIT1 RNA stably localizes to the L1T1 region and plays an important role in transcriptional silencing of the imprinting domain.
3) Misregulation of LIT1 is associated with both Beckwith-Wiedemann syndrome and various cancers including colorectal cancers. To clarify whether L1T1 is correlated with development of cancers, we investigated its expression profiles in esophageal and colorectal cancer. As the results, DNA methylation and histone H3K9 methylation status is not responsible for LOI of LIT1 in colorectal cancers. On the other hand, silencing of imprinted CDKN1C expression was associated with loss of CpG and histone methylation at DMR-L/77 in esophageal cancer, suggeting that LIT1 may be important in the development of this tumor.

Research Products

• [Journal Article] Loss of imprinting of PEG1/MEST in lung cancer cell lines. (2004)
  • Author(s): Nakanishi, H.et al.
  • Journal Title: Oncol.Rep. 12 Pages: 1273-1278
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Silencing of imprinted p57^<KIP2> gene expression is associated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer. (2004)
  • Author(s): Soejima, H.et al.
  • Journal Title: Dncogene 23 Pages: 4380-4388
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Coordinate downregulation of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines. (2004)
  • Author(s): Maegawa, S.et al.
  • Journal Title: DNA Resarch 11 Pages: 37-49
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Imprinting analysis of 10 genes and/or transcripts in a 1.5-Mb MEST-flanking region at human chromosome 7q32. (2004)
  • Author(s): Yamada, T.et al.
  • Journal Title: Genomics 83 Pages: 402-412
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dicer is essential for formation of the heterochromatin structure in vertebrate cells. (2004)
  • Author(s): Fukagawa, T.et al.
  • Journal Title: Nat.Cell.Biol. 6 Pages: 784-791
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. (2004)
  • Author(s): Yu, W.et al.
  • Journal Title: Nat.Genet. 36 Pages: 1105-1110
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of imprinting of PEG1/MEST in lung cancer cell lines. (2004)
  • Author(s): Nakanishi, H., Suda, T., Katoh, M., Watanabe, A., Igishi, T., Kodani, M., Matsumoto, S., Nakamoto, M., Shigeoka, Y, Okabe, T., Oshimura, M., Shimizu, E.
  • Journal Title: Oncol.Rep. 12 Pages: 1273-1278
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Silencing of imprinted p57^<KIP2> gene expression is associated with loss of lustone H31ysine 9 methylation at DMR-LIT 1 in esophageal cancer. (2004)
  • Author(s): Soejima, H., Nakagawachi, T., Wei Z., Urano, T., Matsuoka, S., Higashimoto, K., Kitajima, Y., Takeuchi, M., Nakayama, M., Oshimura, M., Miyazaki, K., Joh, K., Mukai, T.
  • Journal Title: Oncogene 23 Pages: 4380-4388
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Coordinate downregulation of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines. (2004)
  • Author(s): Maegawa, S., Itaba, N., Otsuka, S., Kamitani, H., Watanabe, T., Tahimic, CGT., Nanba, E., Oshimura.M.
  • Journal Title: DNA Resarch 11 Pages: 37-49
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Imprinting analysis of 10 genes and/or transcripts in a 1.5-Mb MEST flanking region at human chromosome 7q32. (2004)
  • Author(s): Yamada, T., Mitsuya, K., Kayashima, T., Yamasaki, K., Ohta, T., Yoshiura, K., Matsumoto, N., Yamada, H., Minakami H., Oshimura, M., Niikawa, N., Kishino, T.
  • Journal Title: Genomics. 83 Pages: 402-412
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dicer is essential for formation of the heterochromatin structure in vertebrate cells. (2004)
  • Author(s): Fukagawa, T., Nogami, M., Yoshikawa, M., Ikeno, M., Okazaki, T., Takami, Y., Nakayama, T., Oshimura, M.
  • Journal Title: Nat.Cell.Biol. 6 Pages: 784-791
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. (2004)
  • Author(s): Yu, W, Ginjala, V., Pant, V., Chernukhin, I., Whitehead, J., Docquier, F., Farrar, D., Tavoosidana, G., Mukhopadhyay, R., Kanduri, C., Oshimura.M..Feinberg, AP., Lobanenkov, V., Klenova, E., Ohlsson, R.
  • Journal Title: Nat.Genet. 36 Pages: 1105-1110
  • Description: 「研究成果報告書概要(欧文)」より