Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer

被引:162
作者
Takai, D
Gonzales, FA
Tsai, YC
Thayer, MJ
Jones, PA
机构
[1] USC, Keck Sch Med, USC Norris Comprehens Canc Ctr, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA
[2] USC, Keck Sch Med, USC Norris Comprehens Canc Ctr, Dept Urol, Los Angeles, CA 90033 USA
[3] Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA
[4] Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA
关键词
D O I
10.1093/hmg/10.23.2619
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The methylation status of binding sites of the insulator protein, CTCF, in the H19promoter has been suggested as being critical to the regulation of imprinting of the H19/IGF2 locus located in chromosome 11p15. In this study, we have analyzed the methylation of all of seven potential CTCF-binding sites in the human H19 promoter since the methylation status of these sites has not been reported. We found that all the binding sites except the sixth were hypermethylated whereas only the sixth binding site showed allele-specific methylation in normal human embryonic ureteral tissue. We also analyzed the methylation status of these sites in human-mouse somatic-cell-hybrid clones containing a single copy of human chromosome 11 and which were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) to yield clones which expressed human IGF2 and H19 mutually exclusively of each other. In most of the clones, a correlation between methylation of the sixth CTCF-binding site and expression of IGF2 was observed. Therefore, we analyzed the methylation status of this site in human bladder cancer and found hypomethylation of the paternal allele in two of six informative cases. These results demonstrate that only the sixth CTCF-binding site acts as a key regulatory domain for switching between H19 or IGF2 expression, whereas the other sites are not subject to allele-specific methylation. Loss of methylation imprinting of H19 is linked to hypomethylation of the paternal allele in human bladder cancer, unlike the situation in Wilms' tumor and colon cancer where the maternal allele becomes hypermethylated.
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页码:2619 / 2626
页数:8
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