Uncovering Important Epigenetic Changes in Neuronal Cell Development
Cell Snapshot of Histone Marks
View the Cell Snapshot: Histone Modifications
Dr. Bing Ren at the San Diego Epigenome Center examined epigenetic events that occur during early embryonic development, as stem cells begin to differentiate into specific cell lineages. Dr. Ren’s work shows that distinct epigenetic mechanisms regulate early and late stages of stem cell differentiation. Interestingly, several gene families that are known to play important roles in development were notably lacking in one type of epigenetic mark, called DNA methylation, in early stages of development. Some of these same genes were found to have excess levels of DNA methylation in cancer, suggesting a possible role for epigenetic regulation of developmental genes in several types of cancer.
An additional study by Drs. Bradley Bernstein and Alexander Meissner, from the Reference Epigenome Mapping Center at the Broad Institute, examined epigenomic changes that occur as human embryonic stem cells differentiate into the three germ layers that develop in an embryo: ectoderm (which becomes epidermis, nervous system, eyes, and ears), mesoderm (which becomes muscle, bone, cartilage, the circulatory system, and the urogenital system), and endoderm (which becomes parts of the gastrointestinal tract, the liver, the pancreas, and the lungs). This study revealed several discrete events that occur during differentiation into each germ layer, providing new insight into how human germ layers are specified during development. Additionally, this information may prove useful to scientists who seek to differentiate induced pluripotent stem cells (iPSCs) for the purpose of repairing or replacing a wide range of tissues damaged by disease or injury.
In a separate study, Drs. Bernstein and Meissner, along with colleagues across the Epigenomics Mapping Consortium, systematically mapped global changes in chromatin, the physical structure of DNA and proteins inside a cell. The conformation of chromatin is regulated by epigenetic factors, leading to changes in gene expression (see “A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health”). By generating over 300 chromatin state maps from diverse human tissues and stem cells, the researchers have discovered signature patterns of “active” chromatin, representing genes that are being expressed, versus “repressed” chromatin, representing genes that are not expressed. During development, chromatin changes from a largely accessible state to a more restrictive state. The chromatin state maps reveal that cells of different developmental stages, or exposed to different environmental conditions, can be distinguished by characteristic differences in chromatin state maps. Prior to this study, much of what scientists knew about chromatin states came from studying cell lines derived from various model organisms.
Collectively, these studies provide a wealth of information about epigenetic dynamics in human cells within different tissues, during various developmental stages, and under a variety of environmental conditions. The extensive data sets available in these publications will be a valuable resource for researchers in a wide range of biomedical fields.
From Dr. Bing Ren:
Zhu J, Adli M, Zou JY, Verstappen G, Coyne M, et al. Genome-wide Chromatin State Transitions Associated with Developmental and Environmental Cues. Cell, 2013 Jan. 152(3): 1-13. PMID: 23333102.
Dr. Stamatoyannopolous and colleagues found that some of the genetic variants linked to adult-onset diseases lie in regions of DNA that regulate genes during the early stages of development, providing a potential mechanism to explain the observation that some environmental exposures in utero or during early childhood are known to increase risk of diseases that produce symptoms years or even decades later. The researchers were also able to link genetic variants in non-coding regions with the genes they regulate, which has been a major challenge in genetic studies because the genes are often located a great distance away. In addition, researchers were able to pinpoint which cell types are affected by different diseases. These results provide new insight into disease mechanisms, and suggest novel targets for therapeutics development and disease prevention strategies.
Reference: Tan M, Luo H, Lee S, Jin F, Soo Yang J, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, and Zhao Y. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell September 2011. 146(6): 1016-28. PMID: 21925322.
The program’s website provides information about the program, protocols, information about data standards, and links to a variety of sites where the epigenomic data can be visualized in a genome browser or downloaded for subsequent analysis.
Researchers in the Common Fund’s Epigenomics Program have taken the first step toward this goal. They have determined a high resolution fingerprint of one type of chemical group on the DNA of human embryonic stem cells and have compared it to what is found in fibroblasts, a type of cell found in many tissue types, including skin. They found that the fingerprints varied drastically between the two cell types. In addition, an analysis of limited regions of DNA from induced stem cells yielded a partial fingerprint that showed the same characteristics as in human embryonic stem cells. This discovery yields fundamental knowledge about stem cells and indicates that induced stem cells are molecularly similar to embryonic stem cells. It provides a method to identify cells as stem cells, and it is important for future work in which these cells will be used to regenerate adult tissues.