Gene Packaging is Important in Cancer

Stephen B. Baylin, MD
The Johns Hopkins University Medical Institutions
NIEHS Grant R01ES011858

New NIEHS-supported research from Johns Hopkins University suggests that the packaging of genes may be as important as the genes themselves when it comes to the development and treatment of cancer. The findings point to the three dimensional chromatin packaging around genes formed by tight loops of polycomb group proteins. Chromatin packaging is a complex combination of DNA and proteins that compress the DNA to fit inside the cell nucleus. The effect of the tight packing and polycomb proteins is to keep genes in a low expression state.

The researchers compared embryonic cells to adult colon cancer cells. The gene studied, GATA-4, is packaged by polycomb group proteins. In the embryonic cells the gene is in a low expression state and had no methylation. When the gene received signals for the cells to mature, the protein structures were disrupted and the gene was highly expressed. However, when the same gene was methylated, as is the case in the colon cancer cells, the polycomb protein packaging loops were tighter and there was no gene expression. When the researchers removed the methylation, the cancer cells behaved similarly to the embryonic cells.

DNA methylation is a normal cellular process, but when the normal processes are disrupted and some genes are improperly methylated, it can shut down important tumor suppressing cell functions. Drugs that removed abnormal DNA methylation from genes have been introduced as potential cancer therapies. This research suggests that for these therapies to be fully effective, researchers may need to search for agents that disrupt the polycomb protein loops.

Citation: Tiwari VK, McGarvey KM, Licchesi JD, Ohm JE, Herman JG, Schübeler D, Baylin SB. PcG proteins, DNA methylation, and gene repression by chromatin looping. PLoS Biol. 2008 Dec 2;6(12):2911-27.