Chromatin proteins provide architectural integrity to DNA. Despite their structural role, they do not stay statically bound but release and reform their bonds continuously. Using FRAP to measure protein dynamics, the group showed that chromatin proteins in differentiated cells are exchanged within minutes to hours, whereas ES cells contain a pool of such proteins that turns over at the rate of seconds. The fast-moving protein fraction is present in several types of pluripotent cells but strikingly absent in committed precursor cells. This quick exchange may be what keeps the genome breathing—open and ready to take on any fate.
Frenetic protein activity also seems to be necessary for differentiation. When chromatin proteins were mutated to bind more tightly to DNA, cells failed to differentiate, whereas mutations increasing the pool of loose proteins led to faster than normal differentiation. The team postulates that in ES cells the proteins may be acting as building blocks where regions of silent (nontranscribing) chromatin are formed as the cell differentiates and shuts down unused areas of the genome.
Misteli hints that chromatin protein dynamics is probably just the tip of the iceberg in the search for what distinguishes pluripotent cells from committed ones, and says the group is looking for other properties of chromatin, such as histone modifications, gene activity, and chromatin structure that may differ in ES cells. They are also examining the underlying question of what the mobility might mean for gene expression. “If [ES] chromatin is really more open,” he says, “there might be more transcription.”