The Center of Excellence in Genomic Science (CEGS) at Johns Hopkins is a multi-investigator, interdisciplinary research effort focused on understanding the epigenetic basis of common human diseases, including age-related illnesses, neuropsychiatric disease, and cancer. The CEGS was recently renewed competitively, receiving a $16.8 million grant over 5 years from the National Institutes of Health. Over the past five years, the CEGS has developed new genome-scale tools to explore the idea epigenetic variation may be at least as great between individuals as variations in the DNA sequences themselves. The premise of the CEGS is that understanding the epigenome may help explain how errors occur in normal development and how environmental factors lead to cancer, autism and other disorders.
Key to the success of the CEGS is the integrated collaborative approach involving professors across multiple departments and divisions of the University, as well as key outside collaborators. Leaders of these teams are: Rafael Irizarry, Professor of Biostatistics; M. Danielle Fallin, Associate Professor of Epidemiology; James Potash, Professor of Psychiatry; and John Stamatoyannopoulos, Associate Professor Genome Science (Univ. Washington).
The CEGS has developed genome-scale tools for epigenetic analysis, including Comprehensive High-Throughput Relative Methylation (CHARM) analysis, a quantitative measure of up to 4 million CpG sites throughout the genome, chosen without bias toward functional preconceptions in the literature. Using CHARM, we discovered that most variable DNAm is not in CpG islands but in nearby sequences we term “shores.” We found 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.
Our prior focus on the simple interface between epigenetics and human disease phenotype variation has prepared us now to address the more complex task of including genetic variation. We are developing genome-wide tools to determine the relationship between genetic variation, epigenetic variation and disease simultaneously (hashed area in the Figure on the left). We will apply second-generation sequencing for epigenetic measurement on an epidemiologic scale, apply our methods to the wealth of genetic and phenotypic information now available for many diseases, maximizing the impact of resources available in this renewal by combining them with the enormous investments already made to collect cohort phenotype information and perform genome-wide genotyping. We deliberately drew the hatched area in this figure as the larger fraction of the overlap between genetics and phenotype to emphasize that most genetic findings must be considered in an epigenetic context, and to highlight that the full value of typical genetic epidemiology studies cannot be realized until the complementary epigenetic measures and statistical tools are developed and performed on these samples.
Toward this end, we are continuing to pioneer genome-wide epigenetic technology that is cost effective for large scale analysis of population-based samples, applying our knowledge from the current period to second-generation sequencing for epigenetic measurement, including DNA methylation and allele-specific methylation. We are also pioneering new statistical approaches for quantitative and binary DNAm assessment in populations, including an Epigenetic Barcode. We are developing a new field we call Epigenetic Epidemiology, examining: time-dependence, heritability and environmental relationship of epigenetic marks; heritability in MZ and DZ twins; and the integration of novel genome-wide methylation scans (GWMs) with existing genome-wide association studies (GWAS).
The CEGS also has a strong commitment to increasing minority involvement in genetics and genome sciences and is recruiting gifted minority high school students to the Johns Hopkins Center for Talented Youth where they take Genetics and Genome Sciences and get hands-on laboratory experience during internships at the CEGS laboratories, and ultimately participate in the Minority Summer Internship Program for college students. To date, 32 minority students have passed through our program.
1. Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends in Genetics 20:350-358, 2004.
2. Bjornsson HT, Cui H, Gius D, Fallin MD, Feinberg AP. The new field of epigenomics: implications for cancer and other common disease research. Cold Spring Harbor Symposium on Quantitative Biology 69:447-56, 2004.
3. Callinan PA, Feinberg AP. The emerging science of epigenomics. Human Molecular Genetics 15 Spec No 1:R95-101, 2006.
4. Ladd-Acosta C, Pevsner J, Sabunciyan S, Yolken RH, Webster MJ, Dinkins T, Callinan PA, Fan JB, Potash JB, Feinberg AP. DNA methylation signatures within the human brain. American Journal of Human Genetics 81:1304-1315, 2007.
5. Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature 447:433-440, 2007.
6. Gosden RG, Feinberg AP. Genetics and epigenetics–nature’s pen-and-pencil set. New England Journal of Medicine 356:731-733. 2007.
7. Irizarry RA, Ladd-Acosta C, Carvalho B, Wu H, Brandenburg SA, Jeddeloh JA, Wen B, Feinberg AP. Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Research 18:780-90, 2008.
8. Bjornsson HT, Albert TJ, Ladd-Acosta CM, Green RD, Rongione MA, Middle CM, Irizarry RA, Broman KW, Feinberg AP. SNP-specific array-based allele-specific expression analysis. Genome Research, 18:771-779, 2008.
9. Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA 299:1345-1350, 2008.
10. Potash JB, Buervenich S, Cox NJ, Zandi PP, Akula N, Steele J, Rathe JA, Avramopoulos D, Detera-Wadleigh SD, Gershon ES, DePaulo JR Jr, Feinberg AP, McMahon FJ; NIMH Genetics Initiative Bipolar Disorder Consortium. Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: association with HMG2L1 and TOM1. American Journal of Medical Genetics B Neuropsychiatric Genetics 147:59-67, 2008.
11. Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekstrom TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP. Intra-individual change in DNA methylation over time with familial clustering. JAMA, 299:2877-2883, 2008.
12. 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. The human colon cancer methylome shows similar hypomethylation and hypermethylation at tissue-specific CpG island shores. Nature Genetics, 42:178-186, 2009.
13. Ladd-Acosta C, Feinberg AP. Cancer epigenomics. In: Epigenomics (Martienssen R, Greally J, Ferguson-Smith A, Eds.). New York: Springer, in press.
14. Wen B, Wu H, Bjornsson H, Green RD, Irizarry R, Feinberg AP. Overlapping euchromatin / heterochromatin marks are enriched in imprinted gene regions and predict allele-specific modification. Genome Research 18:1806-1813, 2008.
15. Wen B, Wu H, Irizarry RA, Shinkai Y, Feinberg AP. Large Histone H3 lysine-9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nature Genetics 41:246-250, 2009.
16. Irizarry RA, Wu H, Feinberg AP. A species-generalized probabilistic model-based definition of CpG islands. Mammalian Genome in press, 2009.