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Moving Ahead with an International Human Epigenome Project NATURE|Vol 454|7 August 2008 FEATURE Moving AHEAD with an international human epigenome project A plan to ‘genomicize’ epigenomics research and pave the way for breakthroughs in the prevention, diagnosis and treatment of human disease. Me The American Association for Cancer Figure 1 | Epigenetic Research Human Epigenome Task Force mechanisms. The coding c and structural information and the European Union, Network of in the base sequence of DNA Excellence, Scientific Advisory Board g g is organized in chromatin to form multiple epigenomes. It is now possible to define whole epigenomes, c c DNA cytosine methylation and representing the totality of epigenetic marks g covalent modifications of the in a given cell type. Epigenetic processes are tails of histones and histone essential for packaging and interpreting the Me variants contribute information genome, are fundamental to normal develop- to nucleosomal remodelling ment and are increasingly recognized as being Me machines that render genes and involved in human disease. Epigenetic mech- non-coding RNAs susceptible anisms include, among other things, histone to transcription. Transcription modification, positioning of histone variants, factors (not shown) also play a nucleosome remodelling, DNA methylation, major part in the competence Me and organization of the small and non-coding RNAs (Fig. 1). These epigenome. The AHEAD project mechanisms interact with transcription fac- will map epigenetic marks in a tors and other DNA-binding proteins to regu- defined set of epigenomes. late gene-expression patterns inherited from cell to cell. The patterns underlie embryonic development, differentiation and cell identity, transitions from a stem cell to a committed cell and responses to environmental signals such as hormones, nutrients, stress and damage. Ac Although epigenomic changes are herit- Chromatin remodeller able in somatic cells, drug treatments could Me potentially reverse them. This has significant implications for the prevention, diagnosis and treatment of major human diseases and Histones Transcription for ageing. Diseases to be targeted could include diabetes, cardio pulmonary diseases, Me Histone tails Rett syndrome, other neurological disorders, Ac imprinting disorders, autoimmune diseases Me and cancer, in which missteps in epigenetic Non-coding RNAs programming have been directly impli- Chromosome cated. Indeed, several inhibitors of chroma- tin- modifying enzymes including histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have now been approved by the US Food and Drug Administration or are in clinical trials with good prognosis for tumour regression. Epige- netic therapy is now a reality, but to maximize the potential of such therapeutic approaches, the human epigenome, and we urge the AHEAD project is to provide high-resolution it is crucial that there be a more comprehen- community to join in a coordinated effort in reference epigenome maps. These maps would sive characterization of the epigenetic changes support of the Alliance for the Human Epig- be of great use in basic and applied research, that occur during normal development, adult enome and Disease (AHEAD) to help solve would have an immediate impact on under- cell renewal and disease, and of the relation- the problems of cancer and other intractable standing many diseases, and would lead to ships between genetic and epigenetic variation diseases. Just as the Human Genome Project the discovery of new means to control the and their impact on health. provided a reference ‘normal’ sequence for diseases. Although the project should have a The time is right for a major effort to decode studying human disease, the goal of the human focus, it will be essential to use model 711 FEATURE NATURE|Vol 454|7 August 2008 Box 1 | A European success story European researchers in the as well as 350 laboratories late 1990s were quick to take worldwide that participate in up the fast-emerging field of ongoing activities through the epigenetics, building on early NoE website. Expansion of the discoveries in X-chromosome NoE resulted in the creation of inactivation, Polycomb Associate Members and, most regulation, dosage compensation, importantly, the NETs. Through the imprinting, heterochromatin, NET programme, talented young DNA methylation, nucleosome European investigators in their first modification and RNA interference four years of independent research (RNAi). The Epigenome Network are selected to participate and of Excellence (NoE) was created provided with moderate financial by the European Commission support. The NET programme has in 2004 with the long-term aim been a resounding success and of tackling major epigenetic has given a powerful impetus to a questions in the post-genomic era. cohort of young research talent. Under the direction of Thomas The NoE programme of activities Jenuwein of the Research Institute has promoted a common identity of Molecular Pathology in Vienna, and generated numerous in lay terms are provided in seven momentum achieved should be assisted by Phil Avner of the collaborations through training and languages. Several NoE members nurtured, supported and exploited Pasteur Institute in Paris and mobility programmes, workshops, are involved in biotechnology to broaden connections with Geneviève Almouzni of the Curie meetings and dissemination of companies and technology transfer biotechnology, agriculture and Institute in Paris, the intention was technologies. In 2007 alone, has been the subject of NoE particularly with the biochemical to create a durable structure for the NoE collectively published workshops. and pharmaceutical industries epigenetics research in Europe, some 300 research articles. These achievements have that are such key components promoting collaborations, sharing A major effort has also been resulted from a conjunction of of the European technological technologies and resources, made to reach out to the broader circumstance, hard work and the landscape. With the worldwide and training and fostering the community with a scientific talent assembled by the NoE. interest in epigenetics, this seems development of leaders in the field. website (www.epigenome-noe. Europe is in many respects pre- an inopportune moment for the Now, after four of the five years net), and to the general public, eminent in the field of epigenetics European Commission to reduce planned, the NoE includes an through conferences, newspaper and the NoE could serve as a model support for this research and risk original core of 25 members articles, and a public website for similar programmes worldwide. losing momentum and brainpower. plus 35 associate members and (www.epigenome.eu), where But, as its five-year mandate On the contrary, the opportunity 23 Newly Established Teams news, information, explanations approaches its end, the future of should be seized to forge close (NETs): a total of 83 laboratories of the concepts, significance and the NoE remains uncertain. The links with international efforts such from 12 European countries, applications of epigenetic research organization, coordination and as AHEAD. organisms to obtain mechanistic insights as to Project), chromatin profiling (HEROIC, a computational infrastructure for data shar- the functionality of epigenomic parameters or High-Throughput Epigenetic Regulatory ing and display that puts epigenetic data in ‘codes’. Studying, genome-wide, the increasing Organization In Chromatin), and treatment the hands of non-epigenetic investigators1. number of interacting epigenetic mechanisms of neoplastic disease (EPITRON, EPIgenetic The American Association for Cancer in a spectrum of cell types will involve data Treatment Of Neoplastic Disease). A spe- Research (AACR) organized a Human Epi- generation on a massive scale. An international cial function is provided by the Epigenome genome Workshop in June 2005 and also a project would provide the bioinformatics infra- Network of Excellence (NoE), created by the follow-up workshop in July 2006 that focused structure needed to ensure that epigenom- European Commission in 2004 (see Box 1). on planning an international project to map a ics research can be integrated with genomic In the past few years, there have been defined number of human epigenomes (http:// data, and be utilized efficiently to advance the several efforts to organize the epigenetics www.aacr.org/page9673.aspx)2. The consen- knowledge of human health and disease. Here, research community in the United States sus of workshop participants was that there are we discuss the benefits of the AHEAD frame- and develop the support and structure for a compelling reasons from both scientific and work to coordinate and plan an international human epigenome project. A 2004 National public-health perspectives to initiate a human Human Epigenome Project. Cancer Institute (NCI)-sponsored Epige- epigenome project that could take full advan- netic Mechanisms in Cancer Think Tank tage of advances in several existing US and Early steps concluded that the development of a US European initiatives. Individual investigators have been study- human epigenome project of analogous On the heels of these workshops, the AACR ing epigenetics for several decades; however, scope to the Human Genome Project should Human Epigenome Task Force, a cross-disci- concerted efforts to organize the epigenom- be of the highest priority (http://www.cancer. plinary group of international investigators, ics research community are quite recent, and gov/think-tanks-cancer-biology/page7).
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