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 molecular basis of Beckwith Wiedemann syndrome (BWS), the paradigm of cancer-predisposing disorders caused by an epigenetic mechanism, uncovering the first antisense RNA associated with human disease. In addition, we found that BWS is linked to in vitro fertilization technology. Recently we have developed a mouse model of loss of imprinting in cancer, in which we have found that epigenetic alterations in stem cells increase the risk of malignancy, and suggesting an epigenetic progenitor origin of human cancer.

We are also pioneering genome-scale technology for epigenetics research, 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.

A second 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.

Publications:

DeBaun MR, Niemitz EL, and Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19, Am J Hum Genet, 72:156-160, 2003.

Cui H, Cruz-Correa M, Giardiello FM, Hutcheon DF, Kafonek DR, Brandenburg S, Wu Y, He X, Powe NR, and Feinberg AP. Loss of IGF2 imprinting: A potential marker of colorectal cancer risk. Science, 299:1753-1755, 2003.

Feinberg AP and Tycko B. The history of human cancer epigenetics. Nature Reviews Cancer, 4:143-152, 2004.

Bjornsson H, Fallin D, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends in Genetics, 20:350 358, 2004.

Gius D, Cui H, Bradbury C, Cook J, Smart DK, Shuping Z, Young L, Brandenburg S, Hu Y, Bisht K, Ho AS, Mattson D, Sun L, Munson PJ, Chuang EY, Mitchell JB, and Feinberg AP. Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach, Cancer Cell, 6:361-371, 2004.

Sakatani T, Kaneda A, Iacobuzio-Donahue CA, Carter MD, deBoom Witzel S, Okano H, Ko MSH, Ohlsson R, Longo DL, and Feinberg AP. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science, 307:1976-1978, 2005.

Feinberg AP, Ohlsson R, and Henikoff S. The epigenetic progenitor origin of human cancer. Nature Reviews Genetics, 7:21-33, 2006.

Kaneda A, Wang CJ, Cheong R, Timp W, Onyango P, Wen B, Iacobuzio-Donahue CA, Ohlsson R, Andraos RA, Pearson MA, Sharov AA, Longo DL, Ko MSH, Levchenko A, Feinberg AP. Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Procedings of the National Academy of Sciences, 104:20926-20931, 2007.

Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason, V., Feinberg AP. Intra-individual change over time in DNA methylation with familial clustering. JAMA, 299:2877-2883. 2008.

Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature, 24:433-440, 2007.

Yu W, Gius D, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP*, Cui H*. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature, 451:202-206, 2007. (*co-corresponding authors)

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, in press.