Deciphering and exploiting the regulatory logic of Tbx1 gene expression.

We aim at testing a new idea about how the Tbx1 gene is controlled during early development. This gene produces a protein called TBX1, which guides developing cells to become the appropriate tissues. If a person has only one working copy of Tbx1, instead of two, development does not occur normally, a condition known as haploinsufficiency, and it can cause DiGeorge syndrome. We do not fully understand why this phenomenon exists or how the activity of the gene is regulated. We think that Tbx1 is controlled by a group of DNA switches, called regulatory sequences, that work as a control center for turning the gene on and off as needed. Genes like Tbx1 often have complex control systems involving many interacting parts and feedback loops. We have used advanced tools that let us study thousands of individual cells, looking at both their gene activity and availability. We identified a set of regulatory switches located near the Tbx1 gene. This set includes at least three important sequences and a site that the TBX1 protein can bind to, suggesting that the gene may regulate itself in a feedback loop. When we eliminated each of the three sequences individually, we saw major changes in how Tbx1 is expressed. We now plan to study exactly how these sequences function in specific developing tissues. We’ll also explore whether adjusting these switches could help control Tbx1 activity and possibly reduce the harmful effects of having only one working copy of the gene.