Overview

What is the International Human Epigenome Consortium?

The deciphering of the human genome sequence has helped our understanding of biological processes in health and diseases. However, the way in which the genomic information is organized within the cell, through epigenetic processes, is known to play a major role in regulating gene expression and in controlling specific cellular functions. Epigenetic processes go beyond DNA-stored information and are essential for packaging and interpreting the genome, are fundamental to normal development and cell differentiation, and are increasingly recognized as being involved in human disease.

Epigenetic mechanisms include histone modification, positioning of histone variants, nucleosome remodelling, DNA methylation, and small and non-coding RNAs, among others. In concert with transcription factors and other DNA-binding proteins, these epigenetic mechanisms, which may be inherited from cell to cell, regulate gene expression patterns to govern the development of the > 250 cell types in the human body. While the DNA sequence is identical in almost all of these diverse cell types, their epigenetic profiles are very distinct. The modulation of these epigenetic profiles significantly contributes to embryonic development, differentiation, and cell identity, transitions from a stem cell to a lineage-committed cell, and underlies responses to environmental signals (e.g., hormones, nutrients, stress, and damage). In many respects, the epigenetic interpretation of the genome (i.e. epigenomic information) represents a “second code” that programs and stabilises the DNA-based information in diverse biological contexts.

Mis-steps in epigenomic programming have been directly implicated in common human diseases including but not limited to diabetes, cardiopulmonary diseases, neuropsychiatric disorders, imprinting disorders, inflammation, autoimmune diseases, and cancer as well as in ageing. Importantly, epigenomic changes are potentially reversible by drug treatments. This has significant implications for the prevention and treatment of these major human diseases. Indeed, several inhibitors of chromatin-modifying enzymes, including histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have now been FDA and EU approved and are being used in clinical practice with good prognosis for tumor regression. Therefore, epigenetic-based therapy is now a reality in the clinic. However, to maximize the potential of such therapeutic approaches, it is critically important that there be a more comprehensive characterization of the epigenetic changes that occur during normal development, adult cell renewal, and disease, and of the relationships between genetic and epigenetic variation and their impact on health.

Regenerative medicine is a very promising approach for many diseases. Recently, major progress has been achieved in cellular reprogramming to generate pluripotent cells from human somatic cells. These new sources of pluripotent cells are potentially useful for the production of genetically compatible material for cellular therapy. Reprogramming involves changes in epigenetic profiles and it will be important to have reference epigenome maps of all relevant human cell types to evaluate the importance and the consequences of these epigenetic changes.

Environment and nutrition have strong and durable influences on our health. Differences in epigenetic profiles are known to be induced by environmental and nutrition changes, so that maps for reference epigenomes will greatly broaden our understanding of how the environment and nutrition will modulate epigenetic alterations. This new, non DNA-based, knowledge will have a major impact for novel avenues in preventing and diagnosing disease.

Recent technological improvements allow high throughput mapping of epigenome in a very reproducible and standardized way. It is now possible, with these new technologies, to map the entire epigenome of a human cell. Scientists and representatives of major funding agencies have decided to launch the International Human Epigenome Consortium (IHEC). Just as the Human Genome Project provided a reference ‘normal’ sequence for studying human disease, IHEC will provide high-resolution reference epigenome maps to the research community. These maps will integrate the various epigenetic layers of detailed DNA methylation, histone modification, nucleosome occupancy and corresponding coding and non- coding RNA expression in different normal and disease cell types. The epigenome reference maps will be of great utility in basic and applied research, have an immediate impact on understanding many diseases, and will hopefully lead to the discovery of new means to control them. Although the project should have a human focus, it will be essential to involve model organisms to obtain mechanistic insights as to the functionality of epigenomic parameters or “codes.”

IHEC will coordinate epigenome mapping and characterisation worldwide to avoid redundant research effort, to implement high data quality standards, to coordinate data storage, management and analysis and to provide free access to the epigenomes produced. The expectations are that the outcome of the research carried out by the members of IHEC will be extensive. First and foremost will be the availability of reference human epigenomes to the world-wide research community. Second, will be valuable information on the methods utilized by IHEC members to produce, analyze, and integrate large epigenomic datasets related to health and diseases, in human and in model organisms. Third, it will become possible to compare different human populations thereby evaluating the impact of environment and nutrition on the epigenome. IHEC will facilitate communication among the members and provide a forum for coordination, with the objective of maximizing efficiency among the scientists working to understand, treat, and prevent diseases.