Understanding and targeting epigenetic changes driving cancer development
The Epigenetic Etiology of Human Disease Laboratory led by Keith Robertson, Ph.D., at Mayo Clinic is working to understand how epigenetic modifications are disrupted during cancer initiation and progression, and how detrimental environmental exposures work through the epigenome to promote disease. This work is expected to allow for the development of novel therapeutics and biomarkers to improve outcomes in people with cancer.
The primary focus of the Epigenetic Etiology of Human Disease Laboratory led by Keith D. Robertson, Ph.D., is to understand the role of epigenetics, particularly DNA methylation and hydroxymethylation, in human health and disease.
Epigenetic modifications regulate accessibility and stability of the DNA and ultimately determine how, when and where genetic information is used to specify cellular identity, without altering its primary sequence. Epigenetic marks within the human genome include those that target the DNA, such as methylation and hydroxymethylation, and those that target the histone proteins that package the DNA, such as lysine methylation, acetylation and many others.
Regulated changes to DNA epigenetic marks are essential for normal human development and specification or maintenance of cellular identity. Unique epigenetic profiles impart stem cells with their ability to differentiate into any cell type, despite their DNA content being identical to specialized cell types throughout the body. Similarly, most differentiated cell types within the human body are defined by the unique placement of epigenetic marks that participate in regulation of cell type-specific patterns of gene expression. In human diseases such as cancer, diabetes, cardiovascular disease and neurological disorders, epigenetic marks are subtly to profoundly altered, typically in a disease- and stage-specific manner.
For example, disrupted DNA methylation patterns are a universal feature of tumors: They occur early during tumor development, and they actively contribute to cancer initiation and progression. In fact, many cancers may arise from stemlike cells that have sustained aberrant epigenetic changes due to harmful environmental exposures. The epigenome is thought to act as an interface between factors in our highly variable environment — nutrition, infection, stress, inflammation and exercise are just a few of the factors — and our very static genome, which changes very slowly over evolutionary time scales. In this capacity the epigenome takes inputs from environmental cues and modulates use of the genome. This modulation could serve as a positive adaptive response promoting cellular fitness or result in pathological gene expression changes that predispose individuals to long-term elevated disease risk.
A growing number of Food and Drug Administration-approved and experimental drugs targeting aberrant DNA and histone epigenetic changes are becoming available for patient treatment, clinical trials and laboratory studies. These agents provide novel ways to target tumor cells by restoring normal epigenetic states, because epigenetic modifications, unlike genetic mutations, are reversible as part of their normal biology. Use of such drugs can be tailored to the person's individual epigenetic and genetic landscape (personalized medicine).
In addition, detection of aberrant DNA methylation in DNA derived from bodily fluids such as blood plasma and urine, or stool, holds great promise as a source of noninvasive early detection biomarkers. For example, disease-specific DNA methylation signatures within cell-free DNA (cfDNA) circulating in plasma and released from diseased tissue has emerged as a powerful source of early detection and prognostic biomarkers for cancer and noncancer-related diseases. Since this DNA retains epigenetic marks characteristic of its cell of origin, epigenetic biomarkers can, in principle, identify not only presence of disease, but also the affected tissue or cell type. This permits individuals at most risk to be identified and treatment initiated while the disease is in its earliest and most treatable stage.
The lab's current projects focus on the regulation of epigenetic marks in normal cells, understanding how these processes become disrupted during cellular transformation and determining how we can take advantage of tumor-specific epigenetic changes for novel biomarkers and therapeutic targets.
Learn more about our research focus areas and funding:
About Dr. Robertson
Keith D. Robertson is a researcher trained in biochemistry and pharmacology with appointments in the Department of Molecular Pharmacology and Experimental Therapeutics and the Department of Biochemistry and Molecular Biology at Mayo Clinic's campus in Rochester, Minnesota. He also serves as a professor of pharmacology within the Mayo Clinic College of Medicine and Science. Dr. Robertson's focus on epigenetics, specifically the DNA epigenetic marks, is vital to discovering novel ways to diagnose and treat common human diseases.