High-Resolution 3D Map
Recently, particularly with the developments in the field of epigenetics, the interface between DNA methylation and gene expression has become a vibrant research topic. For many years, it has been known that genes can become switched off by abnormal methylation in cancer. Subsequently, studies that examined the methylome identified many genes that exhibit aberrant methylation in cancer cells, when compared to their untransformed counterparts.
“Most of these events are probably irrelevant and, in all likelihood, they represent the consequence of the cell being a cancer cell, just as it also happens with mutations, many of which are known to be passengers,” says Peter A. Jones, Ph.D., D.Sc., distinguished professor of urology and biochemistry at the University of Southern California.
While the presence of aberrant DNA methylation changes in cancer cells has become relatively easy to explore, a much more challenging aspect is to determine whether these methylation changes are driving the process of malignant transformation or whether their emergence is consequential to it. Dr. Jones and colleagues recently described an approach that facilitates the identification of the epigenetic driver events required for cancer survival.
The investigators hypothesized that the few key chromosomal regions whose methylation is required for cancer cell survival would preferentially remain methylated when global methylation levels are reduced. After surveying residual DNA methylation levels in cancer cells with genetically disrupted DNA methyltransferases and clustering profiles from normal cells and primary cancer tissues, Dr. Jones and colleagues used gene expression meta-analysis to define the regions that are dependent on DNA methylation-dependent gene silencing.
Their strategy helped identify a set of promoters whose methylation is required for somatic cancer cell survival. Some of the respective genes are shared among several tumor types, while others are cancer- or tissue- specific. “The genes identified by this approach have not been previously known as tumor suppressor genes,” notes Dr. Jones.
In addition to helping define and validate the minimal DNA methylation profile that is necessary and functionally relevant for cancer cell survival, this approach advances our knowledge on the molecular events that drive cancer development, and promises to define a new generation of epigenetic therapies, in which the alterations that are being targeted are exactly the ones that the cancer cells rely on for survival.
While over the past 15 years the field of DNA methylation has focused on promoters, there are additional regions where methylation, even though not well understood functionally, could play important biological roles.
“We are looking more globally to see whether the bodies of the genes and the enhancers, which also undergo methylation, but we do not know yet it role at these locations, is important. It is important to look beyond promoters,” says Dr. Jones.
A significant challenge in biomedical sciences emerged when functional genomics developments, which uncovered novel aspects about biological systems, have not been paralleled in pace by drug discovery advances.
“Another problem is that the current strategy of optimizing candidate therapeutic compounds, which relies on a single target, is somewhat dangerous, and measuring the collective response of all relevant genes related to a specific phenotype, which is a much better option, has been technologically challenging,” says Xiang-Dong Fu, Ph.D., professor of cellular and molecular medicine at the University of California, San Diego.