Epigenetics studies heritable changes in gene expression that are not
actually encoded in the DNA of the genome. These effects are mediated by the covalent attachment of chemical groups to DNA and its associated proteins, histones and chromatin. Types of modification include:
methylation
acetylation
phosphorylation
ubiquitination
ADP-ribosylation
Post-translational modifications have been linked to gene regulation (1), cellular stress events (1), aging and DNA repair (2).
Embryonic Development:
DNA methylation is required for normal embryonic development and survival of differentiated cells (3-5). Early in development, the paternal genome is actively demethylated, and the maternal genome is subsequently demethylated, potentially through a passive mechanism (6,7). Methylation then increases in the blastocyst to generate the methylation patterns observed in adults. In addition, genomic imprinting, which is the specific expression of a paternal or maternal gene in placental mammals, is necessary for normal embryonic, neonatal and neurological growth and is mediated by DNA methylation and noncoding RNAs. These imprints are established during sperm and egg development by DNA methyltransferase Dnmt3A and maintained by Dnmt1 isoforms. X inactivation, which is the process of mammalian dosage compensation of X-linked genes, is also mediated by DNA methylation and noncoding RNA (7).
Pathogenesis:
Cancer involves generalized, genomewide hypomethylation and local hypermethylation of CpG islands associated with promoters (8). Demethylation of long interspersed nuclear elements (LINEs), which is a family of repetitive DNA sequences, occurs early in some cancers, and the degree of LINE methylation is often correlated with the degree of malignancy. Cancer patients can vary in the frequency of methylation changes, and those with hypermethylation of multiple genes are proposed to have a CpG island methylator phenotype (CIMP) (9-11), which could impact diagnosis, treatment, and outcomes. In cancer, epigenetic changes are more frequent than genetic mutations and have resulted in cancer specific biomarker discovery (e.g., Septin 9 for colorectal cancer). Although the significance of each epigenetic change is not clear, hundreds to thousands of genes can be epigenetically silenced by DNA methylation.
Therapeutics & Diagnostics:
Epigenetic modifications and enzymes have the potential to be the basis of new therapeutics and diagnostic tests for diseases or syndromes with epigenetic components. To date, a histone deacetylase inhibitor and two DNA methyltransferase inhibitors (azanucleoside drugs) have been approved by the United States Food and Drug Administration to treat T cell cutaneous lymphoma and myelodysplastic syndrome, respectively. Additional drug candidates that inhibit histone deacetylases and DNA methyltransferases are in development (12-14), as are histone methyltransferase inhibitors and DNA methylation inhibitors that do not require incorporation into DNA, like the azanucleoside drugs (15).
The utility of combination therapies and development of more specific, targeted therapies remain areas of interest. In addition, because cancers are frequently associated with hypermethylated tumor suppressor genes and because tumor-derived DNA is present in various, easily accessible body fluids, methylated DNA could be a biomarker for detecting some cancers (16-19). Epigenetic therapies and biomarkers have also been studied and developed for systemic lupus erythematosis (20,21).
Epigenetic abnormalities contribute to the development of other complex diseases such as:
type II diabetes
schizophrenia
autoimmune disease
hypertrophic cardiomyopathy
long QT syndrome
autism
Epigenetic mechanisms may help explain some features of complex diseases, including:
late onset
gender effects
parent-of-origin effects
phenotypic differences between monozygotic twins
fluctuation of symptoms
Future Prospects and Challenges:
The epigenetic code is hypothesized to be the combined effects of histone modifications and DNA methylation on gene expression. While the genetic code in an individual is the same in every cell, the epigenetic code can be tissue- and cell-specific and may change over time because of aging, disease or environmental stimuli (e.g., nutrition, life style, toxin exposure) (22). Cross-talk between histone modifications, DNA methylation or RNAi pathways are being studied in such areas as cancer, X inactivation, and imprinting.
Studying the timing and changes in epigenetic modifications during development and disease has many challenges. In addition, epigenome maps are still being assembled for most organisms. To help support the growth in this exciting field of science, advances in research methodologies must address issues such as:
the reduction in sample size requirements for histone modification studies and biomarker detection
development of better antibodies
development of more reagents and methods that can distinguish 5-mC and 5-hmC
improving highly parallel DNA analyses
developing computational tools to organize and integrate diverse epigenomic data
To help coordinate efforts, resources and funding, three large consortiums or initiatives have been created to date. The Human Epigenome Project began as a mixed academic and industrial consortium in Europe. The Alliance for the Human Epigenome and Disease (AHEAD) was formed by the American Association for Cancer Research Epigenome Task Force and the European Union Network of Excellence Scientific Advisory Board. The United States National Institute of Health established an epigenomics roadmap initiative in 2007.
References:
Huang J., et al. (2006) Nature, 444, 629–632.
Pahlich, S., Zakaryan, R.P. and Gehring, H. (2006) Biochim. Biophys. Acta., 1764, 1890–1903.
Li, E., Bestor, T.H. and Jaenisch, R. (1992) Cell 69, 915-926.
Okano, M., Bell, D.W., Haber, D.A. and Li, E. (1999) Cell 99, 247-257.
Jackson-Grusby, L., Beard, C., Possemato, R., et al. (2001) Nat. Genet. 27, 31-39.
Santos, F., Hendrich, B., Reik, W. and Dean, W. (2002) Dev. Biol. 241, 172-182.
Wutz, A. and Gribnau, J. (2007) Curr. Opin. Genet. Dev. 17, 387-393.
Kim, J.K., Samaranayake, M. and Pradhan S. (2009) Cell. Mol. Life Sci. 66, 596-612.
Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J.G., Baylin, S.B. and Issa, J.P. (1999) Proc. Natl. Acad. Sci. USA 96, 8681-8686.
Weisenberger, D.J., Siegmund, K.D., Campan, M., et al. (2006) Nat. Genet. 38, 787-793.
Ang, P.W., Loh, M., Liem, N., et al. (2010) BMC Cancer 10, 227.
Bolden, J.E., Peart, M.J. and Johnstone, R.W. (2006) Nat. Rev. Drug Discov. 5, 769-784.
Jones, P.A. and Taylor, S.M. (1980) Cell 20, 85-93.
Cheng, J.C., Yoo, C.B., Weisenberger, D.J., et al (2004) Cancer Cell 6, 151-158.
Brueckner, B., Garcia Boy, R., Siedlecki, P., et al. (2005) Cancer Res. 65, 6305-6311.
Qureshi, S.A., Bashir, M.U. and Yaqinuddin, A. (2010) Int. J. Surg. 8, 194-198.
Kim, M.S., Lee, J. and Sidransky, D. (2010) Cancer Metastasis Rev. 29, 181-206.
Despierre, E., Lambrechts, D., Neven, P., Amant, F., Lambrechts, S. and Vergote, I. (2010) Gynecol. Oncol. 117, 358-365.
Martens, J.W., Margossian, A.L., Schmitt, M., Foekens, J. and Harbeck, N. (2009) Future Oncol. 5, 1245-1256.
Ballestar, E., Esteller, M. and Richardson, B.C. (2006) J. Immunol. 176, 7143-7147.
Crispín, J.C., Liossis, S.N., Kis-Toth, K., et al. (2010) Trends Mol. Med. 16, 47-57.
