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Bloomberg Distinguished Professor of Epigenetics
Professor of Medicine, Biomedical Engineering, Oncology, Molecular Biology & Genetics, Psychiatry & Behavioral Sciences, Biostatistics, and Mental Health
Molecular Biology and Genetics
855 N. Wolfe Street
Baltimore MD 21205
Epigenetics in development and disease
Understanding how the information in the genome is utilized is one of the central questions in modern biology. It has become clear that a critical level of gene regulation occurs through the chemical modification of both the DNA itself and the proteins that organize eukaryotic DNA into chromatin. This form of gene regulation, termed epigenetics, refers to cellular “memory” other than the DNA sequence alone, and occurs through mechanisms such as the addition of methyl groups to DNA, as a way of marking specific genes as active or silent. Our laboratory develops integrated methods in molecular genetics, cell biology, and computational analysis and applies them to both basic and translational studies in epigenetics. We have developed several new genomics, biostatistical, and biochemical methods and is applying them to cutting-edge studies of epigenetic mechanisms and disease research.
Some of the projects we’re working on include:
• What are the epigenetic drivers of cancer progression? We are determining how mutations in epigenetic modifier genes alter the epigenetic landscape in normal development and cancer, and increase epigenetic plasticity and tumor cell survival.
• Can epigenetic alterations in cancer be reversed using novel approaches targeted to large blocks of heterochromatin and/or metabolism?
• What are the epigenetic drivers of neuropsychiatric disease and how are they related to brain-region specific developmental epigenetic marks?
• What is the relationship between common DNA sequence variants and tissue-specific epigenetic marks in normal development and disease?
• How do genome and environment interact to cause disease, and how is this mediated by the epigenome? We are attacking head-on the mechanisms through which environment influences gene function, or “GxE”, focusing on extremely important and contemporary exposures highly relevant to human health: diet, environmental toxicants and their relationship to metabolic disorders and cancer.
• What is the mathematical foundation of epigenetic information? We are pursuing our novel idea that genetic variants that control phenotypic variance confer a selective advantage in evolution in an environment that changes, and that the same idea may explain phenotypic plasticity in cancer evolution, with the “hallmarks” of cancer being selected for at the expense of the host. We are developing new information theoretic tools to relate DNA methylation, chromatin structure, and gene sequence to stochastic modeling.
McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, Word AE, Carrer A, Salz TH, Natsume S, Stauffer KM, Makohon-Moore A, Zhong Y, Wu H, Wellen KE, Locasale JW, Iacobuzio- Donahue C, Feinberg AP. Large-scale epigenomic reprogramming links anabolic glucose metabolism to distant metastasis during the evolution of pancreatic cancer progression. Nature Genetics. 2017; 49:367- 376.
Jenkinson G, Pujadas E, Goutsias J, Feinberg AP. Potential energy landscapes identify the information-theoretic nature of the epigenome. Nature Genetics. 2017; 49:719-729.
Vanaja KG, Timp W, Feinberg AP*, Levchenko A* (co-corresponding author). A loss of epigenetic control can promote cell death through reversing the balance of pathways in a signaling network. Molecular Cell 72:60-70, 2018
Feinberg AP. The key role of epigenetics in human disease prevention and mitigation. New England Journal of Medicine 378:1323-1334, 2018.
Rizzardi LF, Hickey PF, Rodriguez DiBlasi V, Tryggvadóttir R, Callahan CM, Idrizi A, Hansen KD, Feinberg AP. Neuronal brain region-specific DNA methylation and chromatin accessibility are associated with neuropsychiatric disease heritability. Nature Neuroscience 22:307-316, 2019.