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09.01.2025 08:04

Cooperation of Ghost-Driving Genes

Sylvia Kreyssel-Minar Kommunikation
Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

A groundbreaking study in Nature Genetics, led by Martin Fischer, laboratory head, and Steve Hoffmann, research group leader at the Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), makes a decisive contribution to understanding how genes are regulated.

Jena. Our genome contains tens of thousands of genes. Like a gigantic orchestra, their interaction is the basis for all vital processes in our body. Errors in their interaction can lead to serious illnesses and are one reason we age. Therefore, biology and medicine researchers are working hard to understand how the orchestra of genes is organized and how genes are activated or deactivated.

A groundbreaking study in Nature Genetics, led by Martin Fischer, laboratory head, and Steve Hoffmann, research group leader at the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), now makes a decisive contribution to understanding how genes are regulated. In collaboration with researchers from the Technical University of Darmstadt and the State University of New York at Albany, the Jena scientists show how so-called convergent promoters act as potent regulators in our genome.

What is convergent transcription, and why is it important?
The 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 investigations in recent years have indicated that the active transcription of a gene is often accompanied by transcription in the opposite direction. 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 latest findings now call this assumption into question.

A surprisingly large 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 the research training group ProMoAge and first author of the study. One of the project's biggest challenges was to prove the spatial proximity of convergent transcription. “We had to prove that the molecules are formed from opposite directions in a very small space,” adds Steve Hoffmann. Flavia Vigliotti and Alexander Loewer from the Technical University of Darmstadt played a decisive role in this experiment. The researchers from Hesse used high-resolution imaging techniques and confirmed that convergent transcription can indeed occur on the same DNA segment.

In the further course of the study, the international research team demonstrated that proteins that initiate the transcription process at one of the two promoters also simultaneously amplify the transcription of the opposite side. Two such proteins, also known as transcription factors, were particularly interesting - p53 and RFX7. Both factors are essential in cancer development and regulate many other genes by interacting with promoters. Therefore, a precise understanding of their mode of action is of immense importance in cancer research. Conversely, it has also been shown that factors such as E2F4, which suppress transcription, 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 the State University of New York at Albany. Convergent promoters create a dynamic “conversation” between opposing regulatory regions, allowing for a more fine-tuned control of gene expression.

Challenging the prevailing understanding of transcriptional interference
For years, researchers worldwide 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 indicated 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 control coordinated gene expression. Instead of interfering with each other, these promoter pairs play a crucial role in the adaptive regulation of gene activity.”

Evolutionary significance: The selection advantage of convergent promoters
The DNA segments of convergent promoters have been exceptionally well preserved in evolution and still show high similarity between different vertebrate species. This result suggests that convergent transcription may have had 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 in length and often in their function,” emphasizes Elina Wiechens.

A new paradigm of gene regulation
The discovery of cooperative convergent promoters opens up new insights into the regulatory architecture of our genome and impacts the methods we use to study the regulation of our genome. Steve Hoffmann explains: “Our work suggests that many 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”. Martin Fischer adds that this is particularly important for regulatory interactions associated with the development of cancer and other diseases.

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Originalpublikation:

Gene regulation by convergent promoters. Elina Wiechens, Flavia Vigliotti, Kanstantsin Siniuk, Robert Schwarz, Katjana Schwab, Konstantin Riege, Alena van Bömmel, Ivonne Görlich, Martin Bens, Arne Sahm, Marco Groth, Morgan A. Sammons, Alexander Loewer, Steve Hoffmann & Martin Fischer. nature genetics. 09. Januar 2025.

DOI: 10.1038/s41588-024-02025-w

https://www.nature.com/articles/s41588-024-02025-w

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Cooperation of Ghost-Driving Genes. (Picture: Katjana Schwab/DALL-E)

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