The rules that cells use to determine which genes they must activate and under what conditions have been further uncovered by scientists at New York University. The findings develop the understanding around how gene variants affect phenotypic traits.

The scientists’ research focussed particularly on one protein, Zelda, which has been found in the past to be responsible for turning on a set of genes necessary to development in an extremely co-ordinated manner.

Gene regulation occurs via sections of DNA lying adjacent to genes and known as enhancers, which read a cell’s environment and integrate inputs into a defined gene activity response.

To find out more about the regulatory logic that exists between enhancers and genes, the researchers examined fruit fly embryos, which use genes similar to those in humans. One particular gene required for nervous development, Dorsal, binds directly to the gene’s enhancer. Zelda also binds to the enhancer, and is thought to boost Dorsal activity, but it is not yet known how this is achieved.

The team mutated the Zelda binding sites and quantified gene response to find that probability, onset and degree of gene activation were all changed, hugely impacting gene activity. Zelda’s activity was isolated, and it was determined that Dorsal protein was enriched at enhancers containing Zelda sites compared to those without them, showing how Zelda strengthens Dorsal activity.

“Not only does the research characterise a newfound element of cellular activity, but it also uncovers the physical parameters that affect gene activation, thus pushing forward our understanding of how genes are regulated in time and space,” Christine Rushlow, a professor of biology at New York University, noted.

“This study has uncovered rules that cells use to make decisions about what genes they activate, when and how much, in response to their environment. We were able to directly observe cells in a decision-making process, and then manipulate and measure a portion of DNA that acts as tiny circuit to make this single decision.”