Keith D. Robertson, Ph.D., focuses on determining how epigenetic marks, especially DNA methylation, are established and maintained in normal cells. He is also interested in how these marks become disrupted and lead to common human diseases such as cancer, diabetes, cardiovascular disease and neurologic disorders.
Epigenetics, which literally 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 the DNA (methylation) and those that target histones, which are proteins that package the DNA (methylation, acetylation and many others). Dr. Robertson is using these epigenetic marks collectively to determine how, when and where the genetic information will be used without altering its composition (such as when genes are turned on or off).
- Mechanisms regulating DNA methylation and DNA hydroxymethylation. In vitro, cell culture and animal models are used to define how the enzymes that methylate and hydroxymethylate human DNA work under normal and disease conditions. Dr. Robertson is specifically studying the DNA methyltransferases (or DNMTs) and ten-eleven translocation proteins (or TETs).
- Mechanisms underlying cancer development by mutations in epigenetic modifiers. There is growing realization that genes regulating epigenetic marks are mutated at high frequency in many human cancers. The way these mutations lead to cancer is likely distinct from traditional tumor suppressor genes, requiring a better mechanistic understanding of how they regulate cell growth. Such studies are also expected to yield novel and more-specific treatments for cancer patients.
- Pharmacoepigenomics. Dr. Robertson is studying the mechanism of action of drugs that target the epigenome, such as 5-azacytidine, and defining how specific epigenetic landscapes modulate drug effect. Whole-genome short hairpin RNA screens are also employed to identify genes that modulate efficacy of epigenetic-based inhibitors.
- Epigenetic etiology of human liver disease and the impact of alcohol and hepatitis viral infection on the epigenome. In this project, cutting-edge methods interrogate DNA methylation and expression patterns across the entire genome of human liver disease samples. This includes those that occur due to chronic alcohol abuse and hepatitis viral infection, such as cirrhotic liver and hepatocellular carcinoma. A long-term goal is to develop noninvasive tests for human liver disease, permitting early detection and treatment.
- The role of epigenetic modifications in stem cell pluripotency. Stem cells are being used as models for examining the role of epigenetic modifications in tissue-specific differentiation and gene expression. The epigenetic landscape of tumor stem cells is also being investigated.
- Immunodeficiency, centromere instability and facial anomalies (ICF) syndrome. ICF syndrome is caused by mutations in the genes DNMT3B and ZBTB24, and possibly in others. The goal of this project is to better understand DNA methylation defects in this disorder and develop a model to study methylation-targeting mechanisms.
Significance to patient care
Epigenetic changes that occur as part of normal development and in specific disease states (such as cancer) are reversible. This is in stark contrast to the DNA sequence (genome), which is static throughout development; the rare changes that do occur are permanent and lead to disease.
Drugs targeting aberrant epigenetic changes exist and many more are in development. These agents provide novel ways to target tumor cells and restore normal epigenetic states. Use of such drugs can be further tailored to the patient's specific epigenetic and genetic landscapes (individualized medicine). In addition, detection of aberrant DNA methylation in bodily fluids holds promise as a noninvasive early detection biomarker. This would allow high-risk patients to be identified and treated in the early stages of disease.
- President, Epigenetics Society, 2005-2007