4. Setting of DNA methylation patterns in embryonic stem cells
As new methylation patterns are established during early embryo development, embryonic stem (ES) cells provide a suitable experimental system for investigating the molecular mechanisms underlying this epigenetic reprogramming process. ES cells possess both DNA demethylation and de novo methylation activities. Each of these opposing activities appears to be targeted to selected DNA sequences. We recently initiated studies on the epigenetic regulation of cancer-germline genes in ES cells.
We found cancer-germline genes to be repressed and methylated in human ES cells (obtained from Dr. D. Melton, Harvard University, MA), as well as in human embryonal carcinoma (EC) cells, the malignant counterparts of ES cells. This suggests that cancer-germline genes are programmed for methylation-mediated silencing in human ES cells. Our group is currently searching to identify the factors that target DNA methylation towards cancer-germline gene promoters in these cells. Loss of function of such factors may be a prerequisite for demethylation and activation of cancer-germline genes in tumors.
Similarly, we found mouse cancer-germline genes to be repressed and methylated in mouse ES cells. Surprisingly however, when in vitro methylated human cancer-germline sequences were transfected into mouse ES cells, the integrated transgenes became demethylated (Loriot et al., Epigenetics, 2008). It appears therefore that mouse ES cells not only lack appropriate factors to induce de novo methylation of human cancer-germline transgenes, but in addition target the demethylation machinery to these sequences. This disparity between mouse and human cancer-germline genes is likely attributable to their poor sequence conservation, especially within regulatory regions. Nevertheless, mouse ES cells offer a valuable experimental model to study the mechanisms of demethylation of human cancer-germline sequences. It is reasonable to propose that at least part of these mechanisms also contribute to demethylation of these genes in tumors.
To know more... (pdf chapter of the last de Duve Institute report)
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