Our genetic material contains tens of thousands of genes. Like a gigantic orchestra, their interaction is the basis for all vital processes in our body. Errors in this interaction can lead to serious illnesses and are one of the reasons why we age. Researchers in biology and medicine are therefore working hard to understand how the orchestra of genes is organized and how genes are activated or deactivated.
A recent study in "Nature Genetics" led by laboratory head Martin Fischer and Steve Hoffmann, research group leader at the Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) and for Bioinformatics for Aging Processes at the University of Jena, now provides a decisive contribution to understanding the regulation of our genes. In collaboration with researchers from TU Darmstadt and the State University of New York at Albany, the Jena researchers show how so-called convergent promoters act as powerful regulators in our genome.
What is convergent transcription and why is it important?
A first step in gene activation is the directed transcription of genetic information from the beginning to the end of the gene. This process produces an RNA molecule which, under certain conditions, can later be translated into proteins. The transcription of a gene is controlled by a so-called promoter region, which is located directly before the start of the gene. More detailed studies in recent years have indicated that the active transcription of a gene is often accompanied by transcription in the opposite direction. In this case, two promoter regions "face" each other, both of which initiate transcription. This so-called convergent transcription resembles a genomic ghost ride and was long considered an obstacle to gene expression. The new findings now call this assumption into question.
A surprising number of genes are affected by such ghost runs."This phenomenon can be observed in about 25 % of all active transcription start sites," explains bioinformatician Elina Wiechens, PhD student at the FLI and in the ProMoAge Research Training Group and first author of the study. One of the biggest challenges of the project was to prove the spatial proximity of convergent transcription."We had to prove that molecules are formed from opposite directions in a very small space," adds Steve Hoffmann. Flavia Vigliotti and Alexander Loewer from TU Darmstadt played the decisive role in this experiment. The researchers from Hesse used high-resolution imaging techniques and confirmed that convergent transcription can indeed take place on the same section of DNA.
In the further course of the study, the international research team was able to prove that proteins that trigger the transcription process at one of the two promoters also strengthen the transcription of the opposite side. Two such proteins, also known as transcription factors, were of particular interest - p53 and RFX7. Both factors play an important role in the development of cancer and regulate a large number of other genes through their interaction with promoters. A precise understanding of their mode of action is therefore of immense importance in cancer research. Conversely, it has also been shown that factors such as E2F4, which suppress transcription, also negatively influence the opposite partner by binding to a promoter.
"The significance of this discovery is immense. When two promoters work together instead of acting in isolation, the possibilities for gene regulation multiply," explains Morgan Sammons from Albany. Convergent promoters create a dynamic "conversation" between opposing regulatory regions and enable fine-tuned control of gene expression.
Understanding of transcription interference called into question
For years, researchers around the world assumed that convergent transcription leads to so-called "transcriptional interference". This occurs when the enzyme complexes required for transcription move towards each other.It is as if two wide trucks are about to collide on a narrow road," explains Martin Fischer.At least one of the two enzyme complexes must interrupt transcription. The new study from Jena, Darmstadt and Albany puts a question mark behind this idea.
At the beginning of the research project, the team observed a positive correlation between the transcripts of convergent promoters. These results provided the first indication that pairs of promoters cooperate and do not work against each other, as previously assumed. Martin Fischer explains:"This research expands our understanding of gene regulation by showing how convergent promoters drive coordinated gene expression. Instead of interfering with each other, these promoter pairs play a crucial role in the adaptive regulation of gene activity."
The selection advantage of convergent promoters
The DNA segments of convergent promoters have been particularly well conserved during evolution and still show a high degree of similarity between different vertebrate species. This result suggests that convergent transcription may have provided an evolutionary advantage. Convergent promoters allow multiple RNA transcripts to be regulated from a single site. This structure increases the flexibility to control gene expression and may have helped to better adapt to changing conditions.Convergent promoters can even lead to different gene products. These gene variants differ not only in length, but also to some extent in their function," emphasizes Elina Wiechens.
A new paradigm of gene regulation
The discovery of cooperative convergent promoters provides new insights into the regulatory architecture of our genome and influences the methods we use to study the regulation of our genome. Steve Hoffmann explains:"Our work suggests that a large number of genes have a second, previously unknown promoter. Expanding the definition of the promoter and analyzing the previously neglected ’ghost driver’ can help us to improve our understanding of gene regulation. This is particularly important for regulatory interactions that are associated with the development of cancer and other diseases, adds Martin Fischer.
