|Department Affiliations||Gilman Scholar and King Fahd Professor of Medicine, Oncology, Molecular Biology/Genetics, and Biostatistics; Director, Center for Epigenetics, IBBS|
|SOM Address||570 Ranfos|
Our laboratory is studying how genetics and the environment conspire to cause diseases, 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.
Finally, we are leading a study of the changes between identical twins in space, comparing samples from Scott Kelly in the International Space Station to his identical twin Mark on Earth, to assess longitudinal changes in these very different environments.
- 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. PMID 20720541
- 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. PMID 21725293
- 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. PMID 21706001
- 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.PMID 22983211
- 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. PMID 23334450
- Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nature Reviews Cancer 13:497-510, 2013.
- Multhaup ML, Seldin MM, Jaffe AE, Lei X, Kirchner H, Mondal P, Li Y, Rodriguez V, Drong A, Hussain M, Lindgren C, McCarthy M, Naslund E, Zierath JR, Wong GW, Feinberg AP. Mouse-human experimental epigenetic analysis unmasks dietary targets and genetic liability for diabetic phenotypes. Cell Metabolism 21:138-149, 2015.
- Feinberg JL, Bakulski KM, Jaffe AE, Trygvadottir R, Brown SC, Goldman LR, Croen LA, Hertz-Picciotto I, Newschaffer CJ, Fallin DM, Feinberg AP. Paternal sperm DNA methylation associated with early signs of autism in an autism-enriched cohort. Int J Epidemiol 2105 Apr 14. pii: dyv028 [Epub ahead of print].PMID 25878217