Determining a Stem Cell’s Fate
What happens to a stem cell at the molecular level that causes it to become one type of cell rather than another? At what point is it committed to that cell fate, and how does it become committed? In a study that marks a major step forward in our understanding of stem cells, a team of researchers from the California Institute of Technology (Caltech) have traced the stepwise developmental process that ensures certain stem cells will become T cells - cells of the immune system that help destroy invading pathogens.
“[This] means that in genetic terms, there is nothing left hidden in the system,” says Ellen Rothenberg, the principal investigator on the study.
The researchers studied five stages in the cascade of molecular events that yields a T-cell - two before commitment, a commitment stage, and then two following commitment. They identified the genes that are expressed throughout those stages, including transcription factors, which code for regulatory proteins and turn particular genes on and off. They found that a major regulatory shift occurs between the second and third stages, when T-cell commitment sets in.
“We were able to ask, ‘Do T-cell genes turn on before the genes that promote some specific alternative to T-cells turn off, or does it go in the other order? Which genes turn on first? Which genes turn off first?’” Rothenberg explains. “In most genome-wide studies, you rarely have the ability to see what comes first, second, third, and so on, in a developmental progression. And establishing those before-after relationships is absolutely critical if you want to understand such a complicated process.”
In the image above, the bars summarise the epigenetic markers correlated with RNA-expression levels for each of about 20,800 known genes in the mouse genome. The left column shows epigenetic markers correlated with activation, the middle shows repression markers, and the right shows the RNA levels expressed by the corresponding genes. Reading across each row, genes that change expression or epigenetic markers during T-cell development change colour. Below the first figure is an image of a mouse embroynic stem cell.
Read more here and in the April 13th issue of Cell: “Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T-cell identity.”