For many stargazers, shooting stars aren’t just glowing bits of rock that suddenly appear, flit across the sky, and blink out of sight. They’re signs of things to come—if they can be interpreted rightly. Cellgazers may begin feeling the same way about developing cells, that is, cells that are more mature than stem cells, but not yet fully differentiated.
In their intermediate stages, developing cells may display differences in gene expression that are as individual as they are fleeting. Although these short-lived differences tend to be overlooked, they may have significant long-term effects. They may, for example, help explain the origin of complex traits and diseases.
Such possibilities are being entertained by cellgazing scientists based at the University of Chicago and Johns Hopkins University. They say that if you look only at undifferentiated or mature cell types, you’ll miss highly dynamic changes in gene expression that occur during cell differentiation. To glimpse such changes, the scientists analyzed RNA sequence data from 16 time points in human stem cells as they developed into cardiomyocytes, or heart muscle cells. In the process, the scientists identified hundreds of expression quantitative trait loci (eQTLs), sections of DNA that are associated with differences in gene expression between individuals.
“Those associations … appear at one point and never again during development, and they might actually be important to the phenotype of the mature tissue and maybe even disease,” said Yoav Gilad, PhD, chief of genetic medicine at the University of Chicago. “But unless you study those particular cell types at that particular time, you’ll never see them.”
Gilad’s laboratory collaborated with a scientific team led by Alexis Battle, PhD, an associate professor of biomedical engineering at Johns Hopkins University. Together, the Gilad and Battle laboratories found patterns in the RNA they sampled every day, for 16 days, from the cells of 19 different human cell lines. Patterns emerged, but not all at once.
Detailed findings appeared June 28 in the journal Science, in an article titled, “Dynamic genetic regulation of gene expression during cellular differentiation.”
“We identified hundreds of dynamic eQTLs that change over time, with enrichment in enhancers of relevant cell types,” the article’s authors wrote. “We also found nonlinear dynamic eQTLs, which affect only intermediate stages of differentiation and cannot be found by using data from mature tissues.”
The fleeting differences that occur during development could help explain differences in risk for complex diseases such as cancer, heart disease, or diabetes that aren’t caused by a single genetic mutation. Instead, these complex diseases are likely caused by dozens, if not hundreds, of subtle genetic mutations combined with interactions with lifestyle and the environment. On their own, these small mutations don’t affect your overall health, but together they can elevate risk for particular diseases. The new research shows that these small genetic differences could impact gene expression at many points along the way.
“We think a lot of the relevant molecular changes that can ultimately explain your risk profile are not going to occur in your mature tissues of the heart, liver, or pancreas that we can sample from adults,” Gilad noted. “They’re probably occurring somewhere much earlier.”
The process of taking stem cells from a person, coaxing them into different kinds of mature cells—while periodically sampling RNA expression along the way—is still time consuming and expensive, so the findings of this study won’t immediately turn into a diagnostic tool. But Gilad says as researchers learn more about what these “shooting star” differences in gene expression mean, they may be able to spot the final genetic signatures they leave in mature tissues. That way, if they saw a certain pattern in the genome, for example, they might know it meant there was a particular level of expression on a certain day of development for those specific cell types.
“We can now think in another dimension,” Gilad declared. “Instead of taking a human and sampling everything you see in front of you, we now know there’s a history of how we got here, and some of those differences can’t be observed anymore.”