Alliance for the Human Epigenome and Disease (AHEAD) Proposal for an International AHEAD Pilot Project

Epigenetic processes are essential for the packaging and utilization of the genome and are fundamental to normal human development. Epigenetic control comprises a variety of mechanisms including histone modifications, histone variants, nucleosome remodeling, DNA methylation, and RNAi components. Synergistic hierarchies between these mechanisms and combinations of pathways dictate alterations in chromatin structure as they occur during cell type differentiation, transitions from a stem cell to a committed cell, and responses to environmental signals. Missteps in epigenetic programming have been directly implicated in major human diseases including Rett syndrome, imprinting disorders, aging, autoimmune diseases, and cancer. Although epigenomic changes are heritable in somatic cells, they are potentially reversible by drug treatments, and this has significant implications for the prevention, diagnosis, and treatment of these diseases. Indeed, several chromatin modifying enzymes (e.g., HDAC and DNMT inhibitors) have now been FDA approved or are in clinical trials with good prognosis for tumor regression: epigenetic therapy is now a reality. To maximize its potential, however, it is critically important that there be a more comprehensive characterization of the epigenetic changes that occur during normal development and disease and a better understanding of the relative relationships between genetic and epigenetic variation and their impact on health.