Andrew P. Feinberg, M.D., M.P.H.
Our laboratory is studying the epigenetic basis of normal development and disease, including cancer, aging, and neuropsychiatric illness. 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. Over the last few years, our laboratory has pioneered the field of epigenomics, i.e. epigenetics at a genome-scale level, founding the first NIH-supported NIH epigenome center in the country, and developing many novel tools for molecular and statistical analysis. Several discoveries and avenues of research have arisen from our epigenome center: CpG islands “shores,” that drive many of the gene expression differences that distinguish normal tissues from each other and from cancer; the first map of the methylome in normal hematopoietic development, as well as in induced pluripotent stem cell (iPSC) reprogramming, discovering that iPSC retain an epigenetic memory of their cell of origin. We are now determining the epigenetic limitations of complete reprogramming to an ES-cell like state, and how to circumvent these limitations.
A major focus is on a chromatin-related finding that much of the genome is organized into large heterochromatin regions with specific posttranslational modifications of histones, extending to 1 megabase or more, and associated with the nuclear lamina. These “LOCKs”, for Large Organized Chromatin K (lysine) modifications, expand during differentiation from stem cells. A huge surprise is that these LOCKs also correspond to large domains of hypomethylation that may characterize all cancers and lead to hypervariable gene expression. We are testing the idea that regulation of LOCKs helps mediate normal development and is disrupted in cancer. For example, dimethylation of H3K9Me2 appears necessary for epithelial-mesenchymal transition, a key step in stem cell development, differentiation, response to injury, and cancer invasion.
Translational epigenetic projects include 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. Another project addresses schizophrenia, a common, profoundly disabling disorder that is already subject of intensive genetic studies. Here we are applying novel tools developed in our epigenome center, 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.
We are also pursuing a novel model of genetically driven stochastic epigenetic plasticity in evolution and development, which may help to explain Lamarckian-like inheritance, reconciling epigenetics with Darwinism. Using the honeybee as a model to test these ideas, he has uncovered the first evidence for methylation-mediated reversible behavior in a whole organism, the honeybee. This same model has led to the recent discovery of genetic variants increasing methylation variability in autoimmune disease, which helps to explain the relationship between genetics, epigenetics, the environment and disease.
- 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.
- 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. Epigenetic memory in induced pluripotent stem cells. Nature 467:338-342, 2010.
- McDonald OG, Wu H, Timp W, Doi A, Feinberg AP. Genome-scale epigenetic reprogramming during epithelial to mesenchymal transition. Nature Structural & Molecular Biology 18:867-874, 2011.
- Hansen, KD Timp W, Corrada Bravo H, Sabunciyan S, Langmead B, McDonald OG, Wen B, Wu H, Liu Y, Diep D, Briem E, Zhang K, Irizarry RA, Feinberg AP. Increased variation in epigenetic domains across cancer types. Nature Genetics 43:768-775, 2011.
- Herb B, Wolschin F, Aryee M, Langmead B, Amdam G, Feinberg AP. Reversible switching between epigenetic states in honeybee behavioral subcasts. Nature Neuroscience 15:1371-1373, 2012.
- Liu Y, Aryee JM, 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, Ekstrom TJ, Feinberg AP. Epigenome-wide association data implicates DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nature Biotechnology 31:142-147, 2013.