Common Fund Researchers Detail Epigenomic Changes during Development
Most cells in the human body contain the same DNA, yet different types of cells have vastly different shapes, sizes, and functions. How do these differences arise? Chemical modifications to DNA and DNA-associated proteins, called epigenetic modifications, help instruct a cell to express only a sub-set of genes, giving rise to different characteristics for different cell types. Epigenetic regulation of gene expression changes during development, and can also change as a result of environmental exposures, pharmaceuticals, aging, and diet. Some epigenetic changes promote health and normal development, while others may contribute to a variety of diseases. Three recent publications in the journal Cell from the Epigenomics program’s Reference Epigenome Mapping Centers reveal important insights about epigenomic changes that take place during development, as non-specialized stem cells differentiate into specific cell types, such as heart, brain, skin, and many more.
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.
Read more about the Epigenomics program here.
From Dr. Bing Ren:
Xie W, Schultz MD, Lister R, Hou Z, Rajagopal N, et al. Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells. Cell, 2013 May 7; http://dx.doi.org/10.1016/j.cell.2013.04.022 . PMID: 23664764.
From Drs. Bernstein and Meissner:
Gifford CA, Ziller MJ, Gu H, Trapnell C, Donaghev J, et al. Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells. Cell, 2013 May 7; http://dx.doi.org/10.1016/j.cell.2013.04.037 . PMID: 23664763.
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 31; 152(3): 1-13. PMID: 23333102.