Predicting the future; which gene when

Cells carry out different functions according to a developmental plan by expressing different combinations of genes, and scientists can now predict when these genes will be switched on or off.

Fluorescence microscopy images of fruit fly: During the early stages of development (top) a CRM 1070 is active (red) in the mesoderm (green) – the tissue gives rise to all muscle types. At a later developmental stage (middle), the same CRM is active (red/pink) in the embryo’s body wall muscle (blue), but not in its gut muscle (green). At the same time (bottom), CRM 5570 (red), drives development in the gut muscle (green) but not in the body wall muscle (blue).

Gene expression is controlled by transcription factors - molecules which bind to stretches of DNA called cis-regulatory molecules (CRMs) to switch the relevant gene on or off.  Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany can now accurately predict when and where different CRMs will be active.

The study – carried out by biologist Robert P Zinzen, computer scientist Charles Girardot and statistician Julien Gagner – combined detailed experimental data about when and where transcription factors are binding to CRMs with a computational approach to forecast CRM activity.

“What’s exciting for me is that the study shows that it is possible to predict when and where the genes are expressed, which is a crucial first step towards understanding how regulatory network drive development,” said Eileen Furlong, who headed the study.

Scientists identified and recorded binding profiles – the combinations of transcriptions factors binding at different times and places – of around 8000 CRMs involved in regulating muscle development in the fruit fly Drosophila.  The activity of a number of such CRMs had previously been studied and grouped into classes according to type of muscle and the developmental stages they were active in.  A computer was trained to unravel these binding profiles and search the 8000 newly identified CRMs for ones with similar binding profiles – these were predicted to have similar activity patterns, implying they are involved in development of the same muscle type.

The scientist tested their predictions and found that the regulatory code in which one binding profile leads to on pattern of CRM activity is not actually that straightforward.  CRMS with different binding profiles can have similar patterns of activity.  The fact that different combinations of transcription factors can regulate the same development process means that if some transcription factors or CRMs are lost during an organism’s evolution, it can still develop into the correct muscle.