Genome-wide analysis of genomic impinting in cancer

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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.