During the first hours of an embryo's development, specialised molecules called pioneer transcription factors unravel parts of its DNA to activate the encoded genes. Which gene is activated and when has to follow a set schedule so that genes that are only needed at later stages of development are not activated too early - such as those that trigger the differentiation of specialised cell types. A previously unknown mechanism that enables this precise control of genes, has been discovered by a research team led by developmental biologist Dr. Daria Onichtchouk and theoretical physicist Prof. Dr. Jens Timmer. Both scientists are members of the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies at the University of Freiburg, which promotes interdisciplinary projects like this. The current study, led by the two scientists, describes a previously unknown mechanism by which two activating transcription factors block each other's activities. The same factors that trigger the expression of early genes can thereby also prevent the premature expression of later genes. The findings have been published in Nature Communications.
Like the interaction of two keys and a lock
The researchers discovered this in two zebrafish transcription factors, Pou5f3 and Nanog. "We knew that these transcription factors interact, but it was assumed that they could only make DNA more accessible, not less," explains Onichtchouk. The researchers have now been able to show that there are indeed two possible modes of interaction: Pou5f3 and Nanog can either function synergistically to activate a gene, or antagonistically, inhibiting gene expression. "How they interact depends on the sequence of the DNA region they bind to," says Onichtchouk. "This newly-discovered antagonistic interaction is what inhibits the expression of hundreds of genes during early stages of development."
The Freiburg researchers' study shows that Pou5f3 and Nanog synergistically activate those genes where they both act as activators, but have an antagonistic regulatory effect for those genes that can be activated by only one of them. In their publication, the researchers compare this interaction to two keys and a lock: If one of the keys fits into the lock but cannot turn it, it will block the correct key from entering. "Now we know a lot more about the mechanisms by which transcription factors have context-dependent function," Onichtchouk summarises their finding. "This adds to the known complexity of gene regulation, but also brings us an important step closer to a complete understanding."
