Last updated: March 30, 2015
Scientists create a new "roadmap" for the human epigenome
By Sara Cassidy, M.S., Ph.D.
Postdoctoral Fellow, NHGRI
The human genome sequence is fixed, which means that the genome in every cell of the body should have the same DNA code. What then, makes an eye cell different from a liver cell?
The difference is in how the individual genes of the genome are regulated and expressed-in essence how and when they are turned "on" and "off".This is what determines the differences between each cell. These changes are largely controlled by epigenetics
Epigenetics describes modifications to the genome that can be passed on to future cells.These changes do not alter the nucleotide sequence of the DNA-the As, Gs, Ts, and Cs that make up our genes. Rather, they modify the "backbone" that supports the DNA sequence. These modifications influence when and how often a gene is active. For example, certain pancreatic cells need the gene that encodes for insulin to be easily accessible (for the cell to transcribe into the insulin protein). But a hair follicle cell would not need insulin to be accessible. In this way, each different cell and tissue type of the human body has a different epigenome.
Mapping of the epigenome began with the ENCyclopedia Of DNA Elements (ENCODE) project launched in 2003. The project seeks to discover and study all epigenomic elements, which are the actual chemicals that are attached to the backbone and control the function of our genes. Unfortunately, its clinical application has been limited, since most of its results cover a small number of cell types. The February Genome Advance of the Month is about how the Roadmap Epigenomics Project aims to fill this gap by cataloguing the epigenome of many different cell types in the human body. In this way, the project hopes to increase our understanding of how the epigenome contributes to health as well as disease.
The Roadmap Epigenomics Consortium published its first set of results on February 19, 2015 in the journal Nature. The group analyzed the epigenomes from a variety of adult human cell types, like brain versus kidney, and cell subtypes, such as cells from different regions of the brain. The group analyzed these cells from both healthy individuals, as well as from patients with cancer, neurodegenerative and autoimmune diseases. They also described the epigenomes of stem cells and included the data from the existing ENCODE project in their final analysis. The results are reference epigenomes from 127 different types of tissue and cells. All the data, including the standards and protocols used to obtain the data, are free to the public and can be found online.
The research team generated five papers that highlight new insights into epigenomics and its importance in development and disease. In one paper, a team headed by Michael Ziller, a postdoctoral fellow at Harvard University and graduate research assistant at the Broad Institute of MIT and Harvard, modeled how neurons grow in a cell culture from stem cells - cells that have the capacity to mature into any cell type. Another group led by Alexander Tsankov (also from the Broad) defined the epigenomic signatures that give rise to the first major split in cell lineage within stem cells during embryonic development (ectoderm, endoderm and mesoderm - the cells that will go on to form the nervous system, organs, and muscles respectively). These insights will allow researchers to define how the epigenome provides the "recipe" to mix the correct genes to make different cell types.
Other teams of scientists from the project studied how the epigenome might impact specific diseases. Kyle Farh (also from the Broad) and colleagues studied genetic variation in the DNA-changes in the As, Gs, Ts, and Cs-that interacts with epigenetic chemicals and how those changes could be linked to autoimmune disease. A team led by Paz Polak (again from the Broad) studied epigenomic changes in cancer cells. They found that they could predict the kinds of mutations of a particular cancer based on the epigenome of the type of cell from which the cancer most likely originated. This means the epigenome of the cancer's ancestral cell has a large influence on which genes within a tumor mutate over time. Importantly, these predictions did not hold when the researchers assessed cancer-cell lines, the standardized cultured cells grown in laboratories, which are often studied as models for cancer. This means that the epigenome has important implications in cancer that may not be applicable for study in laboratory-adapted cancer-cell lines.
Lastly, Elizabeta Gjoneska of MIT, and colleagues, studied a model of Alzheimer's disease in mice to map epigenetic changes in the brain during neurodegeneration. They found that the altered epigenome in the mouse brain was similar to samples from deceased Alzheimer's patients. This altered epigenetic pattern was not seen in tissue from adults that did not suffer from Alzheimer's disease. Therefore, this insight may lead scientists to new targets for drug discovery to combat Alzheimer's and other neurodegenerative diseases.
Even with this vast new understanding of the epigenome, there are many questions still left to answer. For instance, how does the epigenome change as cells-and people-age? Can we use these data to better predict cancer risk in the population? Additionally, while 127 different types of cells are a very good start to understanding the epigenomic landscape, the human body is composed of thousands of different types of cells. Many of these cells are still being discovered, and each has a specialized function in the body.
Much like the final Human Genome Project sequence that was first published in Nature 14 years ago, the Roadmap Epigenomics Project will likely produce more questions than answers for some time. However, armed with this new information, researchers will be able to study more specific details about the genomic origins of human development, health and disease.
Read the studies:
Roadmap Epigenomics Consortium, et al. Integrative analysis of 111 reference human epigenomes. Nature, 518; 317-330. 2015
- Farh, KK, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature, 518;337-343.
- Gjoneska, E, et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature, 518;365-369.
- Polak, P, et al. Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature, 518;360-364.
- Romanoski, CE et al.Roadmap for regulation. Nature, 518;314-316.
- Tsankov, AM, et al. Transcription factor binding dynamics during human ES cell differentiation. Nature, 518;344-349.
- Ziller, MJ, et al. Dissecting neural differentiation regulatory networks through epigenetic footprinting. Nature, 518;355-359.
Posted: March 30, 2015