TY - JOUR
T1 - Methylation of multiple genes in gastric glands with intestinal metaplasia
T2 - A disorder with polyclonal origins
AU - Mihara, Mami
AU - Yoshida, Yukinari
AU - Tsukamoto, Tetsuya
AU - Inada, Ken Ichi
AU - Nakanishi, Yukihiro
AU - Yagi, Yukiko
AU - Imai, Kohzoh
AU - Sugimura, Takashi
AU - Tatematsu, Masae
AU - Ushijima, Toshikazu
N1 - Funding Information:
The authors are grateful to Dr. E. Okochi-Takada for her critical reading of the manuscript. This study was supported by a grant-in-aid for Human Genome and Tissue Regeneration from the Ministry of Health, Labor and Welfare; and the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
PY - 2006/11
Y1 - 2006/11
N2 - Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2′-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention.
AB - Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2′-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention.
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U2 - 10.2353/ajpath.2006.060552
DO - 10.2353/ajpath.2006.060552
M3 - Article
C2 - 17071588
AN - SCOPUS:34047112167
SN - 0002-9440
VL - 169
SP - 1643
EP - 1651
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -
