There's more than one way to suppress a gene – and a new discovery by Technion scientists could lead to a revolutionary new method of regulating genetic activity.
In a study published in the scientific journal Nature Communications, assistant professor Roee Amit, a faculty member at Technion's Faculty of Biotechnology and Food Engineering, along with colleagues, described a mechanism in which a protein can intervene physically between a gene and a factor attempting to activate it.
Previously unknown, this mechanism could enable scientists to develop methods to suppress diseases like cystic fibrosis and sickle-cell anemia, as well as more common diseases that are caused by gene activity or mutations, such as many forms of cancer.
"We verified this model through experimentations conducted on 300 synthetic regulatory sequences in bacteria, and it led us to establish this new concept," said Amit. "We now believe that this mechanism evolved as an effective mechanism for genetic silencing."
Genetic suppression is a biological term that refers to the repression of genetic activity by the cell. Through direct protein function, living cells know how to activate genes through a process known as gene regulation, and to "turn them off" or suppress them, through a process known as repression. Researchers have been experimenting with ways to activate or deactivate genes in order to control diseases, but as each gene is activated in its own way, devising an overall method to regulate genes via that intervention has been very challenging.
During research on direct protein function, the team discovered that there were other factors that seemed to prevent gene expression via physical concealment — that is, through a protein that prevents the interaction between the gene and the factor attempting to activate it.
"The concealing protein can be thought of as a tall man sitting in front of you in the cinema," said Amit. "Another analogy is that of a solar eclipse. In fact, this can be described as a kind of 'genetic eclipse' where some proteins settle on a DNA segment at a point on the gene which conceals the factor that is supposed to activate it, effectively suppressing the gene."
If this is so, this physical mechanism of gene suppression should be predictable since, unlike with their function, the physical contours of genes are similar. To test out the theory, the team conducted an experiment: computing the probability that a protein-bound DNA molecule will "loop" (a process that sets off DNA transcription, the first step of gene expression), and using synthetic enhancers (mutations to induce change in a gene) to test the model's predictions in bacteria. After checking hundreds of such enhancers, they applied them to native genomes using a computer program that examined how the mechanism affected specific genes.
As this method of gene suppression is new, much more research is needed – but the initial research was good enough to qualify the team for a €4 million grant from the Future and Emerging Technologies Open program of the European Commission's Horizon 2020 program. The team will expand to five research groups working together to decipher the principle regulatory codes of bacteria, yeast, mammalian cells and flies, in an effort to further understand physical gene suppression – and how it can be applied in humans to prevent disease.
"The regulatory code is a type of programming language through which the genome is able to control gene expression in terms of location, timing and intensity," said Amit. "The study will make use of innovative DNA printing technologies in order to rewrite the code and examine the output of synthetic applications in living cells."
The researchers hope to decipher the genomic syntax of living cells by writing tens of thousands of synthetic control sequences.