Andrew Feinberg, M.D., MPH
King Fahd Professor of Medicine, Oncology, Molecular Biology & Genetics, School of Medicine
855 N. Wolfe St.
Baltimore, MD 21205
BA, The Johns Hopkins University, 1973
Our laboratory is studying the epigenetic basis of normal development and disease, including cancer, aging, and neuropsychiatric illness. Epigenetics involves changes in DNA and chromatin structure that are remembered by the cell when it divides, such as DNA methylation, genomic imprinting, and histone modification. Epigenetics is important because many of the differences between a germ cell and a somatic cell, or two different tissue types, or a cancer and a normal cell, involve epigenetic changes rather than mutation in the DNA sequence. Early work from our group involved the discovery of altered DNA methylation in cancer, as well as common epigenetic (methylation and imprinting) variants in the population that may be responsible for a significant population-attributable risk of cancer. This has led to a major cancer epigenetics translational study to introduce epigenetic testing for colon cancer risk. We are also investigating the epigenetic basis of neuropsychiatric diseases, including schizophrenia and autism.
We are also pioneering genome-scale technology for epigenetics research, and applying this to human disease including cancer, in work supported by three major interdisciplinary research grants. We are home to a Center of Excellence in Genome Sciences (CEGS) from the NIH, to develop novel tools for genome-wide epigenetic analysis, applicable to disease generally. Work in the CEGS is an interdisciplinary collaboration involving molecular biologists, biostatisticians, epidemiologists and clinicians in the Schools of Medicine and Public Health, as well as a program for minority high school students in the Center for Talented Youth at Johns Hopkins. We are applying novel genome-wide tools to common diseases, including bipolar disorder and autism. This work has led to the discovery of CpG island "shores," and that aberrant methylation in cancer involves roughly equal gains and losses of DNA methylation at these shores, and involves much the same sequences involved in normal differentiation of widely disparate tissues. Under the CEGS, we have also discovered Large Organized Chromatin K9-modifications, or "LOCKs," which are tissue-specific regions of lysine modification in histone H3, and that may provide a mechanistic basis for epigenetic memory during cell division, as well as aberrant epigenetic programming in cancer.
Another major research program involves the first comprehensive study of the newborn epigenome, and its relationship to the genotype of the child and the parents, prenatal exposure to nutritional requirements such as folate, as well as toxins, and the outcome of epigenetic change in children at familial risk of autism. Our third major epigenetics study addresses schizophrenia, a common, profoundly disabling disorder that is already subject of intensive genetic studies. Here we are applying novel tools developed in our CEGS, such as CHARM, to understand the epigenetic contribution in a large case-control study, and to relate epigenetic changes to underlying genetic variation, and to identify any heritable epigenetic change.
The laboratory is also heavily involved in developing new paradigms for the intersection of developmental biology, molecular biology and mathematics. One result of that work is a new model for an epigenetic role in evolution, in which stochastic epigenetic variance per se is hereditary and is a driving force of development, evolutionary adaptation and disease. The model has made specific predictions about the epigenetic basis of cancer that have proven correct experimentally, and may lead to radically new approaches to early diagnosis and therapy.
Recognition and Leadership Roles
Selected Recent Publications
Irizarry R, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash J, Sabunciyan S, Feinberg AP. Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genetics, 41: 178-186, 2009
Wen B, Wu H, Shinkai Y, Irizarry RA, Feinberg AP. Large organized chromatin K9-modifications (LOCKs) distinguish differentiated from embryonic stem cells. Nature Genetics, 41:246-250, 2009.
Doi A, Park I-H, Wen B, Murakami P, Aryee MJ, Irizarry R, Herb B, Ladd-Acosta C, Rho J, Loewer S, Miller J, Schlaeger T, Daley GQ, Feinberg AP. Differential methylation of tissue- and cancer-related CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells, and fibroblasts. Nature Genetics, 41:1350-1353, 2009.
Feinberg AP, Irizarry RA. Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proceedings of the National Academy of Sciences USA, 107 Suppl 1:1757-1764, 2009.
Feinberg AP. The Epigenesis of an Epigeneticist. In Medicine, Science and Dreams (Schwartz D, Ed.). Springer: New York, 2010.
Ji H, Ehrlich LIR, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Kim K, Rossi DJ, Inlay MA, Serwold T, Karsunky H, Ho L, Daley GQ, Weissman IL, Feinberg AP. A comprehensive methylome map of lineage commitment from hematopoietic progenitors. Nature, 467:285-290, 2010.
Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, Kim J, Aryee MJ, Ji H, Ehrlich LI, Yabuuchi A, Takeuchi A, Cunniff KC, Hongguang H, McKinney-Freeman S, Naveiras O, Yoon TJ, Irizarry RA, Jung N, Seita J, Hanna J, Murakami P, Jaenisch R, Weissleder R, Orkin SH, Weissman IL, Feinberg AP*, Daley GQ* (*co-corresponding authors). Nature, 467:338-342, 2010.
Feinberg AP, Irizarry RA, Fradin D, Aryee MJ, Murakami P, Aspelund T, Eiriksdottir G, Harris TB, Launer L, Gudnason V, Fallin MD. Personalized epigenomic signatures that are stable over time and covary with body mass index. Science Translational Medicine, 15:49ra67, 2010.
Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, Huo H, Loh YH, Aryee MJ, Lensch MW, Li H, Collins JJ, Feinberg AP, Daley GQ. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nature Biotechnology 29:1117-1119, 2011.
McDonald OG, Wu H, Timp W, Doi A, Feinberg AP. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nature Structure & Molecular Biology,18:867-874, 2011.
Hansen KD, Timp W, Bravo HC, Sabunciyan S, Langmead B, McDonald OG, Wen B, Wu H, Liu Y, Diep D, Briem E, Zhang K, Irizarry RA, Feinberg AP. Increased methylation variation in epigenetic domains across cancer types. Nature Genetics 43:768-775, 2011.
Herb BR, Wolschin F, Hansen KD, Aryee MJ, Langmead B, Irizarry R, Amdam GV, Feinberg AP. Reversible switching between epigenetic states in honeybee behavioral subcastes. Nature Neuroscience 15:1371-1373, 2012.
Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, Reinius L, Acevedo N, Taub M, Ronninger M, Shchetynsky K, Scheynius A, Kere J, Alfredsson L, Klareskog L, Ekström TJ, Feinberg AP. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nature Biotechnology, 31:142-147, 2013.