SUMMARY
Keith D. Robertson, Ph.D., focuses on determining how normal cells establish and maintain epigenetic marks, especially DNA and histone methylation. He also is interested in how these marks become disrupted and lead to common human diseases such as cancer, diabetes, cardiovascular disease, neurological disorders and rare neurodevelopmental syndromes.
Epigenetics, which means "above genetics," is a rapidly growing field poised to have a major impact on human health and patient treatment. Epigenetic modifications include those that target DNA, such as cytosine methylation, and those that target histones, such as lysine methylation and acetylation that package DNA. Dr. Robertson collectively uses these epigenetic marks to determine how, when and where genetic information is used, such as when genes are turned on or off, without altering its composition.
Focus areas
- The epigenome as a link between the environment and human disease. Environmental factors such as hepatitis virus infection or high-fat diets largely drive liver disease and hepatocellular cancer. These exposures preferentially damage the epigenome at early stages of disease. Dr. Robertson seeks to use liver disease as a paradigm for understanding how the environment deregulates epigenetic marks that control gene expression and causes the epigenome to become heterogeneous throughout the liver and promote undesirable cellular phenotypes. He also seeks to understand how the environment leads to stably altered pathological cellular states, even after removal of the environmental driver. This is called epigenetic memory or scarring.
- Mutations in epigenetic regulator genes as drivers of cancer. Genes regulating epigenetic marks mutate across a broad spectrum of human cancers, but we do not understand how these mutations cause cancer. Focusing largely on renal cell cancer, Dr. Robertson studies how mutations in histone methyltransferases such as SETD2 and NSD1 deregulate the epigenome and lead to changes in gene expression. These changes promote aggressive and metastatic cancer cell properties, but they also create novel therapeutic targets. Dr. Robertson expects these studies to yield novel and more specific treatments for patients being treated for cancer.
- Human developmental disorders arising from mutations in epigenetic regulator genes. While full loss of function of epigenetic regulators is common in cancer, in rare cases, disruption of a single copy of an epigenetic regulator during development leads to a group of developmental syndromes known as mendelian disorders of the epigenetic machinery, chromatinopathies or overgrowth with intellectual disability disorders. Dr. Robertson studies how such mutations in genes such as SETD2 and NSD1 lead to Luscan-Lumish and Sotos syndromes, respectively, and how their loss leads to abnormal human development. Dr. Robertson expects these studies to help develop new treatments to mitigate the loss of these epigenetic regulators.
Significance to patient care
Dr. Robertson seeks to understand how the epigenome controls human health and disease. The epigenome is a set of instructions that tell cells how and when to express certain genes. The collection of all a person's genes is known as the genome. It's typically very stable. Sometimes these epigenetic instructions change naturally as part of normal human development. They also can change in adults as part of cancer development. Or they can change after cells are exposed to viruses, poor diet or toxins in the environment.
Since the epigenome can be rewritten — unlike the genome — new treatments are possible. Dr. Robertson's group is working to find changes to the epigenetic instructions that contribute to diseases such as cancer so that they can understand how these cancers develop and discover new treatments that work on the epigenome.
Medicines are available that rewrite or reverse changes to the epigenetic instruction manual that diseases cause. Many more are being created. These medicines offer new ways to treat cancer and genetic syndromes. Dr. Robertson and his lab are uncovering the best ways to use these medicines to help patients and to discover novel medicines that work better and have fewer side effects.
Healthcare professionals can choose from this growing group of medicines to meet a patient's specific needs. This is known as individualized medicine. It also has become possible to find changes in the epigenetic instruction manual in bodily fluids such as blood. This approach could find cancers earlier and with no need for surgery. The Robertson lab is working to discover the combination of epigenetic alterations that are best at finding early-stage cancers so that patients get the treatments they need sooner.
Professional highlights
- President, Epigenetics Society, 2005-2007.