In genetic decision making, proteins learn to listen to each other

Genes are regulated because they need to be. Factors that determine their transcription don’t tend to change, mainly because they have so many specific jobs to do. When scientists intervene in such complex and regimented structures, they tend to break things, creating a mess and making the results hard to understand.

Working with colleagues at the Systems Biology Institute, Gunter Wagner, Professor of Ecology and Evolutionary Biology, and of Obstetrics, Gynecology and Reproductive Sciences has found examples where transcription factors actually change in evolution in spite of their many roles they play.

From their labs on West Campus, the scientists have developed a new perspective on how certain proteins are evolving.

Focusing on the interaction between two proteins, HOXA11 and FOX01, the scientists had previously shown co-dependence in the transcription of mammalian uterine cells. Published in the journal Cell Reports, they recently discovered evolutionary change where the proteins were acting as if to “decide” to become active depending on their physical interaction. This “functional cooperativity” has evolved in step with mammalian pregnancy, with certain proteins playing a role in placental mammals that can’t be found in non-placental mammals.

“When left alone, these proteins inhibit gene expression, but we know they also have the tools to activate target genes,” explains Wagner. Scientists had previously understood this “negative regulation”, assuming that transcription factors in evolution are acting mostly alone.

“Our recent work actually shows that the proteins evolve to actively listen to each other,” continues Wagner. “It is typical to see strong binding between the proteins, but what we have found is really the evolution of a form of directional communication.”

Wagner and his colleagues are, in effect, solving the puzzle of how these highly functioning proteins have learnt new tricks in spite of all the other things they do. Their discoveries lend new insight to pharmacology and the study of fertility and endometriosis, and for female reproductive biology in general.