Virtually every cell in the body carries an identical genome. But how is it possible that each of the body's 200 different types of specialized cells - in the heart, brain, bone, skin and elsewhere - develops from the same DNA instruction book?
As it turns out, reading that instruction book and carrying out its directives are controlled by chemical markers that attach to DNA to activate or silence genes. These chemical markers, known as the epigenome, vary vastly from one cell type to another and, when disrupted, can play a role in the onset of many diseases, from cancer and Alzheimer's disease to diabetes and autism. Probing the epigenome could improve scientists' understanding of the molecular basis of disease and lead to new treatments.
Now, for the first time, researchers have assembled a comprehensive map of the human epigenome. The mapping, by scientists at Washington University School of Medicine in St. Louis and other institutions, includes detailed descriptions of the epigenetic markers in 111 types of cells and tissues. Partial epigenome mapping is available for many other cell types, and new information will be added as it becomes available.
The research is published in the journal Nature. More than 20 additional papers, including three by scientists at the School of Medicine, appear simultaneously in other Nature journals to show how epigenetic maps can be used to study human biology.
"We've only scratched the surface of the human epigenome, but this massive resource marks the beginning of an era," said a principal investigator of the epigenome mapping project, Ting Wang, PhD, assistant professor of genetics. "We can now begin to describe humans in molecular detail.
"We also can look closely at the epigenetic differences between cell types. We don't yet understand what those differences mean or what epigenetic changes drive cell specialization or the initiation of disease. But that's where we're headed. This resource opens up many new doors in biology and the biomedical sciences."
The epigenome also lies at the intersection of the genome and the environment. People have little control over their DNA, but epigenomes are dynamic and potentially can be altered by changes in lifestyle, such as diet and exercise, or by pharmaceuticals. That makes the epigenome a critical player in health and disease.
The mapping initiative, referred to as the Roadmap Epigenomics Program, is funded by the National Institutes of Health (NIH) Common Fund.
"This (resource) 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 S. Collins, MD, PhD. "This outpouring of data-rich publications, produced by a remarkable team of creative scientists, provides powerful momentum for the rapidly growing field of epigenomics."
The new research generated massive amounts of genetic and molecular data, which proved challenging for scientists to access and analyze on a large scale. To overcome those issues, Wang and his Washington University colleagues developed the WashU Epigenome Browser that allows for faster and user-friendly searches of the data.
In a paper published in Nature Biotechnology, Wang describes the Roadmap Epigenome Browser, which is based on the WashU Epigenome Browser and integrates data from the NIH Roadmap Epigenomics Consortioum and the ENCyclopedia Of DNA Elements project, or ENCODE for short.
Now, for example, scientists worldwide can easily search the browsers to study the epigenomes of brain cells from Alzheimer's patients to see how they differ from those of healthy patients. Or they can associate disease-related genetic variations to epigenetic markers in certain cell types.
In a related paper published in Nature Communications, graduate student GiNell Elliott worked with Wang to analyze DNA methylation, an epigenetic mark that typically silences gene expression. Looking across 25 human cell and tissue types, she found over 18,000 regions of the genome in which DNA is partially methylated and potentially can fine-tune the level at which genes are turned on. The discovery is likely to be important in understanding numerous diseases, including cancer, in which DNA methylation is disrupted.
In other work, graduate student Rebecca Lowdon investigated how cells' developmental origins influence epigenomes. She analyzed epigenetic markers in three types of human skin cells, each of which arises from a different embryonic origin, finding that the skin cells did not share a strong epigenetic signature.
Rather, skin keratinocytes from a newborn were epigenetically more similar to adult breast luminal and myoepithelial cells, each of which originate from the same embryonic tissue, compared with other skin cell types. The work, also published in Nature Communications, highlights the diverse nature of epigenetic markers even among cells within the same organ or tissue.