Scientists Identify Molecular Mechanisms for "Stemness"
In order to fit inside the cell nucleus, our DNA is coiled around protein cores, called histones, like beads on a string. The cell can start the process of making a protein from the DNA (transcription) by uncoiling the DNA around a particular histone. Alternatively, cells can block transcription by preventing the DNA from uncoiling. On a molecular level, the accessibility of a particular stretch of DNA plays an important role in determining the cell's characteristics, by controlling which genes are active and which are inactive because they are inaccessible. Three recent reports have increased scientists' knowledge of how stem cells remain undifferentiated yet pluripotent—key characteristics of "stemness."
In one study, scientists observed that important developmental genes in mouse ESCs are blocked when a molecule, called a methyl group, is added to the histone core of the DNA—a process called methylation. Methylation at this site tends to prevent the DNA from uncoiling. At the same time, methylation of another part of the same histone tends to prepare the DNA to uncoil. The scientists called the opposing methylation patterns "bivalent domains." They suggest that bivalent domains keep the ESCs undifferentiated, yet ready to differentiate when needed.
Two related studies, one in mice and one in humans, describe how a group of proteins, called polycombs, block transcription factors that turn on, or activate, important developmental genes in embryonic stem cells (ESCs). By preventing activation of genes essential to further development, polycombs prevent the ESCs from differentiating. Scientists studying human ESCs (hESCs) noted that the same genes blocked by polycombs were simultaneously bound by transcription factors known to be essential for hESC pluripotency, such as Oct4, Sox2, and Nanog. Thus, the same genes are simultaneously blocked yet primed for activation.
All three reports noted that the same genes were being blocked by both methylation and polycombs, while simultaneously being primed for future action by either methylation or by transcription factors such as Oct4, Sox2, and Nanog. These reports have now identified portions of ESC DNA that scientists must study to understand the essentials of "stemness." All studies cite NIH support. Cell 125(2):315–26, laboratory of E.S. Lander; Cell 125(2):301–13, laboratory of R.A. Young; Nature advance online publication, laboratory of R. Jaenisch)