Better Methods to compare gene expression in single cells found

Quantitative Biology Researchers from Northwestern University offered new evolutionary clues into organismal design principles in the face of physical constraints with respect to gene expression.

Since the genes are normally expressed through transcription, this subjects them to the burst of mutations, which have an impact on the biological processes that are carried out by the proteins in the cells. By using a collection of genes in Drosophila, a family of fruit flies, they found that gene expression is regulated by the frequency of these transcriptional bursts.

“It has been known for almost two decades that protein levels can demonstrate large levels of stochasticity owing to their small numbers, but this has never been empirically demonstrated in multicellular organisms during the course of their development.”This work for the first time identifies the role of randomness in altering the outcome of a developmental process.”

Madhav Mani, assistant professor of engineering sciences and applied mathematics at the McCormick School of Engineering. 

A paper outlining the work, titled “The Wg and Dpp Morphogens Regulate Gene Expression by Modulating the Frequency of Transcriptional Bursts,” was published June 22 in the journal eLife. It had a recent study in which the researchers studied the role of stochastic gene expression on sensory pattern formation in Drosophila. By analyzing experimental perturbations of Drosophila’s senseless gene against mathematical models, the team determined the sources of the gene’s stochasticity, and found that the randomness appears to be leveraged in order to accurately determine sensory neuron fates.

Based on this study, the people at Northwestern tried some experimenting on their own, using a technique called single molecule fluorescence in situ hybridization (smFISH) to measure nascent and mature mRNA in genes downstream of two key patterning factors, Wg and Dpp, responsible for the organ development of fruit fly wings. In comparing the measurements to their data models, the researchers found that, while each gene’s pattern of expression is unique, the mechanism by which expression is regulated—which the team named “burst frequency modulation”(mutation levels) – is the same.

Richard Carthew, director of the Center for Quantitative Biology, added that this mode of gene expression regulation was observed for multiple genes, which hints at the possibility of a broader biological principle where quantitative control of gene expression leverages the random nature of the process.

“From these studies, we are learning rules for how genes can be made more or less noisy. Sometimes cells want to harness the genetic noise—the level of variation in gene expression—to make randomized decisions. Other times cells want to suppress the noise because it makes cells too variable for the good of the organism. Intrinsic features of a gene can imbue them with more or less noise.”

Richard Carthew, director of the Center for Quantitative Biology

Although engineers seem intrigued by the results, the biologists think that this is just a discovery and more fundamental knowledge needs to be gained before applying it to the real world.

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