Beyond the Human Genome Project:
Epigenetics and Human Diseases

By Thomas L. Ortel, M.D., Ph.D.

Epigenetics. An epigenetic trait is transmitted independently of the primary DNA sequence but exerts important effects during normal development as well as the development of human disease The best known epigenetic signals include DNA methylation and chromatin remodeling, both of which result in modulation of gene expression. The Presidential Symposium at the 45th ASH Annual Meeting (10:30 a.m. – 12:45 p.m. today) will focus on the topic of epigenetics in hematology. The three speakers will review their research and discuss the relevance of this field to hematology.

Dr. Arthur Beaudet has extensively studied the role of imprinting, the process whereby the expression status of a gene is determined by the parent from which the gene is inherited, in the Angelman and Prader- Willi syndromes. The Angelman and Prader-Willi syndromes are human genetic disorders involving oppositely imprinted genes: Angelman syndrome is caused by maternal deficiency for human chromosome 15q11-q13, whereas Prader-Willi syndrome is caused by the paternal deficiency for the same region. Dr. Beaudet will discuss the process of imprinting, and how this can affect normal embryogenesis and the expression of disease.

Dr. Stephen Baylin investigates the mechanisms underlying epigenetically-mediated gene silencing, including the role of DNA methylation in the development of cancer. Hyper-methylation of CpG islands in the promoter region of a gene mediates silencing of the affected gene, and inactivation of tumor suppressor genes by this mechanism appears to occur frequently in human cancer. From a temporal standpoint, gene silencing events may occur early in tumor progression and provide a permissive ‘substrate’ for subsequent developments that ultimately result in a malignant cell phenotype. Since gene silencing is a reversible event, reactivating silenced tumor suppressor genes may represent a novel strategy for treating patients with cancer in the future.

Dr. Gary Felsenfeld studies the role of chromatin structure in controlling gene expression, with a particular interest in the mechanisms involved in the control of the b-globin locus during erythroid cell development. Nucleosomes are involved in the regulation of gene expression, and specific post-translational modifications of selected histones within the nucleosome, including acetylation, lysine methylation, and other modifications, can modulate this regulatory activity. Epigenetic inheritance of this regulated ‘profile’ involves the maintenance of patterns of histone modification and/or the association of selected chromosomal binding proteins that correlate with a specific expression state (Nature, 2003; 421:448-453). Dr. Felsenfeld will discuss his studies into the epigenetic mechanisms that are essential for normal hemoglobin switching.