Clements E.G.,Johns Hopkins University |
Mohammad H.P.,Johns Hopkins University |
Leadem B.R.,Johns Hopkins University |
Easwaran H.,Johns Hopkins University |
And 3 more authors.
Nucleic Acids Research | Year: 2012
While DNA methyltransferase1 (DNMT1) is classically known for its functions as a maintenance methyltransferase enzyme, additional roles for DNMT1 in gene expression are not as clearly understood. Several groups have shown that deletion of the catalytic domain from DNMT1 does not abolish repressive activity of the protein against a reporter gene. In our studies, we examine the repressor function of catalytically inactive DNMT1 at endogenous genes. First, potential DNMT1 target genes were identified by searching for genes up-regulated in HCT116 colon cancer cells genetically disrupted for DNMT1 (DNMT1 -/- hypomorph cells). Next, the requirement for DNMT1 activity for repression of these genes was assessed by stably restoring expression of wild-type or catalytically inactive DNMT1. Both wild-type and mutant proteins are able to occupy the promoters and repress the expression of a set of target genes, and induce, at these promoters, both the depletion of active histone marks and the recruitment of a H3K4 demethylase, KDM1A/LSD1. Together, our findings show that there are genes for which DNMT1 acts as a transcriptional repressor independent from its methyltransferase function and that this repressive function may invoke a role for a scaffolding function of the protein at target genes. © 2011 The Author(s). Source
O'Hagan H.,Johns Hopkins University |
Wang W.,Johns Hopkins University |
Sen S.,Johns Hopkins University |
DeStefano Shields C.,Program in Molecular and Translational Toxicology |
And 9 more authors.
Cancer Cell | Year: 2011
Cancer cells simultaneously harbor global losses and gains in DNA methylation. We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin. DNMT1 becomes part of a complex(es) containing DNMT3B and members of the polycomb repressive complex 4. Hydrogen peroxide treatment causes relocalization of these proteins from non-GC-rich to GC-rich areas. Key components are similarly enriched at gene promoters in an in vivo colitis model. Although high-expression genes enriched for members of the complex have histone mark and nascent transcription changes, CpG island-containing low-expression genes gain promoter DNA methylation. Thus, oxidative damage induces formation and relocalization of a silencing complex that may explain cancer-specific aberrant DNA methylation and transcriptional silencing. © 2011 Elsevier Inc. Source
MDxHealth | Date: 2013-10-25
Disclosed are methods for detecting expression and/or aberrant methylation patterns in genes such as the gene DCR1 and their potential to diagnose or prognose a cancer or to predict drug resistance/susceptibility. More specifically, the disclosure relates to oligonucleotides, primers, probes, primer pairs and kits to detect genes such as the gene DCR1, and in particular, methylated forms of genes such as the gene DCR1. The disclosure also relates to pharmacogenetic methods to diagnose or prognose a cancer, to determine suitable treatment regimens for cancer, and to determine methods for treating cancer patients based on expression and/or aberrant methylation patterns in genes such as the gene DCR1.
Glaxosmithkline and MDxHealth | Date: 2013-06-13
An oligonucleotide, primer or probe comprises the nucleotide sequences of any of SEQ ID NO. 5, 6, 7, 2, 3, 4, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 25. The oligonucleotides are useful for the detection of the methylation status of a gene, in particular the MAGE-A
MDxHealth | Date: 2012-12-06
Disclosed are methods for assessing the methylation and mutation status of nucleic acid in a sample. The methods provide for methylation-dependent modification of the nucleic acid in a sample, and subsequently nucleic acid amplification processes to distinguish between mutated and non-mutated target sequence.