Salk researchers chart epigenomics of stem cells that mimic early human development
Scientists have long known that control mechanisms known collectively as "epigenetics" play a critical role in human development, but they did not know precisely how alterations in this extra layer of biochemical instructions in DNA contribute to development. Now, in the first comprehensive analysis of epigenetic changes that occur during development, published in Cell, a multi-institutional group of scientists, co-led by Joseph R. Ecker, has discovered how modifications in key epigenetic markers influence human embryonic stem cells as they differentiate into specialized cells in the body.
Scientists have established that the gene expression program encoded in DNA is carried out by proteins that bind to regulatory genes and modulate gene expression in response to environmental cues. Growing evidence now shows that maintaining this process depends on biochemical processes that alter gene expression as cells divide and differentiate from embryonic stem cells into specific tissues. Epigenetic modifications—collectively known as the epigenome—control which genes are turned on or off without changing the letters of the DNA alphabet (A-T-C-G), providing cells with an additional tool to fine-tune how genes control the cellular machinery.
In their study, Ecker and collaborators from several prominent U.S. research institutions examined the beginning state of cells, before and after they developed into specific cell types. Starting with a single cell type, the team followed the cells' epigenome from development to different cell states, looking at the dynamics in changes to epigenetic marks from one state to another. They found that sections of the DNA that activate regulatory genes, which in turn control the activity of other genes, tend to have different amounts of the letters "C" and "G" of the DNA alphabet, depending on when these regulatory genes are turned on during development. On the other hand, genes active in more mature cells whose tissue type is already determined tend to be CG-poor and regulated by DNA methylation. The results suggest that distinct epigenetic mechanisms regulate early and late states of embryonic stem cell differentiation.
"Epigenomic studies of how stem cells differentiate into distinct cell types are a great way to understand early development of animals," says Ecker. "If we understand how these cells' lineages originate, we can understand if something goes right or wrong during differentiation. It's a very basic study, but there are implications for being able to produce good-quality cell types for various therapies."