Researchers making efforts to understand the genetic basis of human disease and how modification of gene expression might influence human disease and development now have a new resource at their disposal: the Epigenomics Roadmap.

The project behind the roadmap studied the epigenome, the non-genetic changes that occur to DNA which play a role in the regulation of gene expression. These epigenetic modifications are caused by molecules that bind to DNA or its associated structural proteins, called histones, and can physically block gene expression or unblock access to a section of DNA to enable gene expression to take place.

The roadmap was published in a series of papers in Nature by the NIH Roadmap Epigenomics Program, a large international collaboration which has been carrying out the project for the past eight years. Epigenetic changes have been implicated as playing a role in a wide range of diseases and other conditions from cancer to obesity, and partly help to explain the very different phenotypic outcomes that can occur in organisms with similar genetic backgrounds.

To make the map as comprehensive as possible, research teams from across the globe analysed 111 reference human epigenomes of adult and embryonic tissues and cells, which were either healthy or diseased.

The papers published by the consortium broadly deal with three questions that are pertinent to understanding the role of epigenomes:

  1. How do cells interpret the same set of instructions and differentiate into a variety of tissues early in the development of the organism? These studies focused on defining what epigenomic changes are occurring in tissues that are going through key stages of development.
  2. Can analysis of epigenomes provide the missing link between genomic variation and cellular phenotype? Researchers in this area were trying to understand whether changes in the epigenome explain situations where variants in the genome are linked to a disease, but where these variants aren't in a protein-coding region, or where identical genetic backgrounds result in different outcomes.
  3. How does chromatin modification affect gene expression? Chromatin is made up of DNA wound around histone proteins, which together form a compact structure that enables the genome to fit inside a cell's nucleus. Alterations to chromatin structure can modify gene expression, for example through changes in its three-dimensional organisation, or through modifications to histone proteins that block access to DNA.

The work of the Epigenomics Program links to and builds on the work of the ENCODE consortium, which aimed to identify biochemically active regions of the human genome. Similar to the results from ENCODE, the functional roles of many of the mapped epigenetic changes have not been validated yet. However, the data provide a useful resource for scientists interested in disease, and the results from the project have already opened interesting avenues of research.

One example is research carried out on Alzheimer's disease, showing that disease-related changes in the brains of mice with Alzheimer's disease mimicked those changes seen in human brains of those who had recently died from the disease. However some of the epigenetic changes were associated with a boost in activity of genes involved in the immune response, which opens up a potential new avenue of research.

While many of the results sh ow great promise in increasing our understanding of disease, the project in its current form does not have any direct clinical utility. Therefore how the information is used in future research efforts will determine if the roadmap will lead to improved diagnostics and treatments for human diseases. One key observation from the project is that it highlights the complexities of the genetic and epigenetic changes that underlie disease, and provides a framework which researchers can use to focus their efforts in the most promising areas. Time will tell if these efforts will lead to health benefits.