Last Monday, Andrew Feinberg, director of the Center for Epigenetics and chief of the Division of Molecular Medicine, spoke on the epigenetic basis of common human diseases.
Feinberg began by pointing out that while the overall genetic differences between a human and a chimpanzee are small, the genetic differences between different tissue types in the same organism are actually quite significant. Even though the DNA sequence is the same in both a human stomach and eyeball, the pattern of gene expression differs in these two organs — thanks to epigenetics.
Epigenetics involves modifications in gene expression that arise from factors other than changes in DNA sequence. Many of these changes occur in the germ cells (i.e. egg or sperm), and are stable and heritable. A combination of environment and genetics influences epigenetic modifications. A key mechanism of epigenetic modification is the addition of methyl groups to cytosine nucleotides in DNA. In general, highly methylated genes are less likely to be translated into protein and vice versa.
Feinberg and his colleagues believe that epigenetic modifications directly influence the development of diseases including cancers, schizophrenia and bipolar disorder. They developed a method called CHARM, which is capable of analyzing 7 million potential methylation sites in the human genome. They are especially interested in DNA regions where the level of methylation varies between individuals or between healthy cells and diseased cells.
It was believed that the majority of methylation variation is found in CpG islands, which are stretches of DNA with an abundance of adjacent cytosine and guanine nucleotides. However, CHARM discovered that the most dynamic methylation variation was found in the DNA just next to CpG islands, in regions the researchers dubbed “shores.”
“We’re interested in where the variance is and it’s not where everyone had been looking before,” Feinberg said.
Scientists originally believed that by studying variations in the DNA sequences between healthy and diseased individuals, they could identify which genetic variants put a person at risk for a certain disease.
However, there was a much lower correlation between DNA variation and disease than predicted. “DNA sequence variants account for one to 10 percent of the heritable cause of common disease,” Feinberg said. “That doesn’t mean epigenetics is the answer, but it means something else is the answer.”
The researchers discovered that iPSC, or induced pluripotent stem cells, are not completely undifferentiated. They still had DNA methylation patterns resembling the differentiated cells from which they had been derived — whether fibroblasts or bone cells.
They were also able to map the epigenetic landscape of the brain, meaning that they could use a brain cell’s epigenome to determine whether it had come from the hippocampus or the cerebrum, etc. This finding raises the possibility that epigenetics could be used to study mental conditions such as schizophrenia, bipolar disorder or autism.
Feinberg and his collaborators were most interested in the epigenetic changes in cancer cells. They studied the DNA methylation in shore regions of normal liver and colon cells as well as cancerous colon cells. Where normal colon cells have highly methylated shores and normal liver cells have unmethylated shores, canceorus colon cells become unmethylated like normal liver cells.
“What’s really going on epigenetically is that the cancers are confused about what they are,” Feinberg said.
In normal tissues, methylation is distinctive between tissue types. Cancer cells, instead of having a specific methylation pattern, have very varied and indistinct patterns. According to Feinberg, “What defines the cancers is a huge degree of heterogeneity.” In general, once they became cancerous, cells lost their tissue-specific methylation patterns and became much more randomly methylated.
Cancer cells that metastasize, or spread to other tissues, need to be genetically flexible enough to adapt to their new environment. Randomly taking off the methyl groups on DNA will cause some genes to be expressed. There is a chance these genes happen to help the cancer cell metastasize or adapt to its new environment.
Feinberg hypothesized that the flexibility in methylation displayed by cancer cells actually plays an important part in our evolution. Many of the areas in variably methylated regions, or VMRs, in the human genome include genes that are important in embryo development.
Feinberg believes that a certain degree of stochastic (or random) epigenetic change plays important roles in development and evolution.