 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Sep 30, 2014 |
| Title |
RFTS-deleted DNMT1 enhances tumorigenicity with focal hypermethylation and global hypomethylation |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
|
| Summary |
Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in gain of DNMT1 function. However, earlier data suggested that RFTS is required for DNMT1 activity. Here, we determined cellular consequences of RFTS deletion from DNMT1 in immortalized human bronchial epithelial cells. Compared to full-length DNMT1, ectopic expression of DNMT1- ΔRFTS caused greater malignant transformation and enhanced promoter methylation that silenced DAPK and DUOX1 gene expression and increased intensity of promoter methylation across the genome. Strikingly, DNMT1-ΔRFTS also produced genomic hypomethylation and demethylation of Satellite 2 repeat sequences. Because deletion of RFTS is sufficient to induce focal hypermethylation and global hypomethylation in parallel, evidence suggests that the RFTS domain is a target responsible for epigenetic changes in cancer.
|
| |
|
| Overall design |
DNA samples from HBEC3 cells transfected with vector control and HBEC3 cells with full-length and RFTS-deleted DNMT1 were assessed for genome-wide methylation using the microarray-based high resolution HpaII tiny fragment enriched by ligation-mediated PCR (HELP) assay.
|
| |
|
| Contributor(s) |
Wu B, Mei S, Brenner C |
| Citation(s) |
25485502 |
| |
| Submission date |
May 20, 2014 |
| Last update date |
Dec 09, 2014 |
| Contact name |
Duojia Pan |
| E-mail(s) |
[email protected]
|
| Organization name |
UT Southwestern Medical Center
|
| Department |
Physiology
|
| Street address |
6001 Forest Park
|
| City |
Dallas |
| State/province |
Texas |
| ZIP/Postal code |
75235 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18711 |
Nimblegen Human HG19_HELP array [100128_HG19_MKF_HELP_ChIP] |
|
| Samples (3) |
|
| Relations |
| BioProject |
PRJNA248201 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE57829_RAW.tar |
132.0 Mb |
(http)(custom) |
TAR (of PAIR) |
| Processed data included within Sample table |
|
|
|
|
 |
