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Status |
Public on Jan 13, 2017 |
Title |
Gene expression profiling of cancer cells with genetic disruption of DNA methyltransferases [Agilent-026652] |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by array
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Summary |
Maximizing DNA methyltransferase (DNMT’s) inhibition for cancer therapy requires defining the roles and interactions between these enzymes for maintaining the widespread DNA methylation abnormalities in cancer. Combining genetic and shRNA depletion in colon and other cancer cells reveals that DNMT1 is extremely dominant in this maintenance, with DNMT’s 3A and 3B playing minor roles, at all genomic loci including promoters and enhancers. Reducing DNMT1 below a deep threshold level, especially at promoters, is required for reversing abnormal DNA methylation and re-expressing key tumor suppressor genes. Current DNMT inhibitors (DNMTis) are challenged, at tolerable patient doses, for achieving such reductions. We introduce a new approach in which reducing levels of the DNMT targeting protein, UHRF1, complements low DNMTi doses to DNA demethylate and reactivate expression of such genes.
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Overall design |
To understand precisely how the three DNMT’s, 1, 3A, and 3B, interact for maintaining DNA methylation abnormalities in cancer. We perfomed genome-wide DNA methylation and gene expression anaylses in colon cancer and other cancer cell lines following a series of genetic and shRNA depletions of each enzyme. Our data revealed that DNMT1 overwhelmingly plays the essential maintenance role. Even with combined deletions of the proteins, lowering DNMT1 below a threshold level is required for maximal loss of DNA methylation at all genomic regions and is required for maximally reversing promoter DNA promoter DNA hypermethylation with associated re-expression of key tumor suppressor genes.
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Contributor(s) |
Baylin SB, Tsai H, Cai Y |
Citation(s) |
28232479 |
Submission date |
Jan 04, 2017 |
Last update date |
Jan 09, 2018 |
Contact name |
Stephen B Baylin |
E-mail(s) |
sbaylin@jhmi.edu
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Organization name |
Johns Hopkins University
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Street address |
1650 Orleans St. Suite 541
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City |
Baltimore |
State/province |
MD |
ZIP/Postal code |
21209 |
Country |
USA |
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Platforms (1) |
GPL13497 |
Agilent-026652 Whole Human Genome Microarray 4x44K v2 (Probe Name version) |
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Samples (8)
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This SubSeries is part of SuperSeries: |
GSE93136 |
Cancer cells with genetic disruption of DNA methyltransferases |
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Relations |
BioProject |
PRJNA360119 |