Genome-wide analysis of genomic impinting in cancer

癌症基因组印记的全基因组分析

• 批准号: 14026029
• 负责人: OSHIMURA Mitsuo
• 金额: $ 18.56万
• 依托单位: Tottori Univeisity
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14026029/
• 关键词: cancer; genomic imprinting; DMR; epjgenetics; chromatin; FISH; LIT1; IGF2; エピジェネティクス; IGF; RNA; MAR; ゲノム刷り込み; DNAメチル化; インプリントセンター

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.

众所周知，多种遗传和表观遗传变化影响癌症的发生和发展。为了了解印迹基因在肿瘤中的功能作用，我们研究了1)新印迹基因的分离，2)LIT1印迹基因的功能分析，3)胶质瘤、食管癌和结直肠癌等恶性细胞中印迹基因的分析。1)我们已经鉴定出143个人类差异甲基化区DMR位点。此外，我们利用人类单染色体杂交体分离出2个新的印迹基因，它们表现出父本和母本等位基因特异性表达。此外，我们发现在一些胶质瘤细胞系中观察到这些印迹基因的GOI（印迹增益）。这一结果表明，印迹基因的下调可能在胶质瘤的发展中起重要作用。2)作为kcnq10t1的产物，印迹非编码RNA LIT1参与了人类染色体Ilpl5.5上一个印迹簇的顺式限制性沉默。虽然该基因座是印迹中心（imprinting center， IC），但LIT1基因产物的功能尚不清楚。RNA原位杂交提供的证据表明，LIT1 RNA稳定地定位于L1T1区域，并在印迹结构域的转录沉默中发挥重要作用。3) LIT1的失调与Beckwith-Wiedemann综合征和包括结直肠癌在内的多种癌症有关。为了阐明L1T1是否与癌症的发展相关，我们研究了它在食管癌和结直肠癌中的表达谱。结果表明，DNA甲基化和组蛋白H3K9甲基化状态与结直肠癌中LIT1的LOI无关。另一方面，印迹CDKN1C表达的沉默与食管癌中DMR-L/77位点CpG和组蛋白甲基化的缺失有关，这表明LIT1可能在该肿瘤的发展中起重要作用。

项目成果

Dicer is essential for formation of the heterochromatin structure in vertebrate cells

• DOI: 10.1038/ncb1155
• 发表时间: 2004-08-01
• 期刊: NATURE CELL BIOLOGY
• 影响因子: 21.3
• 作者: Fukagawa, T;Nogami, M;Oshimura, M
• 通讯作者: Oshimura, M

Imprinting analysis of 10 genes and/or transcripts in a 1.5-Mb MEST-flanking region at human chromosome 7q32.

• DOI: 10.1016/j.ygeno.2003.08.016
• 发表时间: 2004-03
• 期刊: Genomics
• 影响因子: 4.4
• 作者: Takahiro Yamada;K. Mitsuya;Tomohiko Kayashima;K. Yamasaki;T. Ohta;K. Yoshiura;N. Matsumoto;Hideto Yamada;H. Minakami;M. Oshimura;N. Niikawa;T. Kishino

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.: "Silencing of imprinted p57^<KIP2> gene expression is associated with loss of histone H3

Soejima, H.、Nakakawachi, T.、Wei Z.、Urano, T.、Matsuoka, S.、Higashimoto, K.、Kitajima, Y.、Takeuchi, M.、Nakayama, M.、Oshimura.M..宫崎

Maegawa, S., Itaba, N., Otsuka, S., Kamitani, H., Watanabe, T., Tahimic, CGT., Nanba, E., Oshimura.M.: "Coordinate downregulatiou of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines."DNA Resarch. (in press).

Maekawa, S.、Itaba, N.、Otsuka, S.、Kamitani, H.、Watanabe, T.、Tahimic, CGT.、Nanba, E.、Oshimura.M.：“协调下调新型印记转录物 ITUP1 与

Yuan, J., Luo, RZ., Fujii, S., Wang, L., Hu, W.Andreeff, M., Pan, Y.Kadota, M., Osimura.M., Sahin, AA., Issa, JP., Bast RC Jr., Yu, Y.: "Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast

Yuan, J.、Luo, RZ.、Fujii, S.、Wang, L.、Hu, W.Andreeff, M.、Pan, Y.Kadota, M.、Osimura.M.、Sahin, AA.、Issa,