Tight Packaging Shuts Down Tumor Suppressor Genes

A publication stressed the importance of considering the three dimensional structure of DNA and its associated chromatin packaging when assessing the link between tumor suppressor gene expression and cancer development.

Investigators at Johns Hopkins University (Baltimore, MD, USA) examined the relationship between structure and expression of the gene GATA-4 in embryonic cells and in mature colon cancer cells. They concentrated on two factors that modulated expression of the gene: chromatin packaging and degree of methylation.

They reported in the December 2, 2008, issue of the journal PLoS Biology that chromatin packaging was characterized by the interaction of GATA-4 DNA with Polycomb group proteins (PcG). Polycomb-group proteins are a family of proteins first discovered in fruit flies that can remodel chromatin such that transcription factors cannot bind to promoter sequences in DNA. In humans, abnormal levels of PcG proteins correlate with the severity and invasiveness of several cancer types.

In embryonic cells, GATA-4 was packaged by PcG proteins, in a low expression state, and had no DNA methylation. When the gene received signals for cells to mature, the PcG loops loosened and the gene became highly expressed. However, when the same gene was abnormally DNA methylated, as is the case in adult, mature colon cancer cells, the PcG packaging loops were tighter and there was no gene expression. Treatment of the cancer cells with drugs designed to de-methylate DNA caused the PcG the loops to loosen somewhat, back to the state of an embryonic cell, and some gene expression was restored.

"We think the polycomb proteins combine with abnormal DNA methylation of genes to deactivate tumor suppressor genes and lock cancer cells in a primitive state,” explained senior author Dr. Stephen B. Baylin, professor of oncology at Johns Hopkins University. "These tight loops touch and interact with many gene sites folding it into a structure that shuts off tumor suppressor genes. Demethylating agents, drugs that target and remove abnormal DNA methylation from genes, have been introduced as potential new cancer therapies. For these therapies to be fully effective, researchers may also need to look for agents that disrupt PcG loops.”

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