Beyond the two-dimensional genomic universe lies the three-dimensional epigenomic universe—subtler, shiftier, but still chartable. Having just explored the molecular genetic “epi,” the chemical modifications that occur on, over, near, or at (but not in) the genome’s string of DNA bases, researchers affiliated with the NIH’s Roadmap Epigenomics Program (REP) published two dozen scientific papers presenting the first comprehensive maps and analyses of the epigenomes of a wide array of human cell and tissue types. These papers described the distribution of methylation marks and histone modifications that constitute the genetic epi, and related the changing architecture of chromosomal units with the modification of gene activity.

Eight of the papers appeared online February 18 in Nature, with the balance appearing in six other journals of the Nature Publishing Group. According to a press release issued by the NIH, these papers describe how the epigenomes of more than 100 types of cells and tissues were mapped, and provide new insights into which parts of the genome are used to make a particular type of cell. REP data, the release added, can be found at the National Center for Biotechnology Information website.

The unveiling of the REP data was also heralded by releases issued by universities and research institutions that participated in the mapping. For example, the University of California, San Francisco, quoted its own Joseph F. Costello, Ph.D., director of one of four NIH Roadmap Epigenome Mapping Centers (REMCs), as follows: “The DNA sequence of the human genome is identical in all cells of the body, but cell types—such as heart, brain or skin cells—have unique characteristics and are uniquely susceptible to various diseases. By guiding how genes are expressed, epigenomes allow cells carrying the same DNA to differentiate into the more than 200 types found in the human body.”

Dr. Costello added that the new data will hasten a merging of genomic and epigenomic perspectives that was already underway: “You've had cancer researchers studying the genome—the role of mutations, deletions, and so on—and others studying epigenomes. They've almost been working on parallel tracks, and they didn't talk to each other all that much. Over the past five or six years, there's been a reframing of the discussion, because the most recurrent mutations in cancer affect epigenomic regulators. So the way mutations in the genome play out is through epigenomic mechanisms, and major pharmaceutical companies now view epigenomes as an important target.”

The cluster of papers that appeared in Nature included four articles and four letters. The titles of the articles are as follows:

  • Integrative analysis of 111 reference human epigenomes
  • Chromatin architecture reorganization during stem cell differentiation
  • Genetic and epigenetic fine mapping of causal autoimmune disease variants
  • Transcription factor binding dynamics during human ES cell differentiation

The titles of the letters are as follows:

  • Integrative analysis of haplotype-resolved epigenomes across human tissues
  • Dissecting neural differentiation regulatory networks through epigenetic footprinting
  • Cell-of-origin chromatin organization shapes the mutational landscape of cancer
  • Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease

This outpouring of epigenomic information “represents a major advance in the ongoing effort to understand how the 3 billion letters of an individual's DNA instruction book are able to instruct vastly different molecular activities, depending on the cellular context,” said NIH Director Francis Collins, M.D., Ph.D. “This outpouring of data-rich publications, produced by a remarkable team of creative scientists, provides powerful momentum for the rapidly growing field of epigenomics.”

Almost all human cells have identical genomes that contain instructions on how to make the many different cells and tissues in the body. During the development of different types of cells, regulatory proteins turn genes on and off and, in doing so, establish a layer of chemical signatures that make up the epigenome of each cell. In the Roadmap Epigenomics Program, researchers compared these epigenomic signatures and established their differences across a variety of cell types. The resulting information can help us understand how changes to the genome and epigenome can lead to conditions such as Alzheimer's disease, cancer, asthma, and fetal growth abnormalities.

Researchers can now take data from different cell types and directly compare them. “Today, sequencing the human genome can be done rapidly and cheaply, but interpreting the genome remains a challenge,” said Bing Ren, Ph.D., professor of cellular and molecular medicine at the University of California, San Diego, and co-author of the Nature paper and several of the associated papers. “These 111 reference epigenome maps are essentially a vocabulary book that helps us decipher each DNA segment in distinct cell and tissue types. These maps are like snapshots of the human genome in action.”

“The epigenome—chemical modifications to chromosomes and 3D chromosomal structure—is not just a linear object,” Dr. Ren added, as quoted in a release issued by UC San Diego. “The epigenome is a 3D object, folded in a hierarchical way, and that should affect how we think about many aspects of human development, health and disease.”