Study highlights role of disordered protein interactions in gene expression
A team led by researchers at Baylor College of Medicine and IOCB Prague has uncovered a new piece of the puzzle of how gene expression is orchestrated. Published in the journal Science, the findings reveal a novel mechanism that coordinates the assembly of components inside cells that control gene expression. The mechanism not only is essential for normal cell function, but also has been implicated in cancer, neurodegeneration and HIV infection, and could suggest new ways to treat these conditions.
The researchers show this attachment plays an important role in the early stages of gene expression.
“We first determined that TNDs and TIMs bound together in ‘test tube’ type of experiments, but it was really exciting to see that they bind to each other in living cells, validating the relevance of our observations in living systems,” Cermakova said. “We also determined that the TND-TIM interactions are highly specific.”
“I was surprised to see that IWS1, a protein previously thought to be a secondary player in the transcription elongation machinery, acts as a central organizer of these factors,” said Hodges, a member of Baylor’s Dan L Duncan Comprehensive Cancer Center.
“We found that IWS1 uses specific TND-TIM interactions to coordinate the activities of many transcription regulators at the same time, making it appear like a conductor at a symphony that keeps all the factors working in harmony and close by,” Veverka said.
The team also explored the consequences of disrupting a single unstructured protein region on the harmony of the transcription elongation process.
“Hundreds of genes with important functions were altered when we disrupted even a single unstructured region,” Hodges said. “The first step of gene expression started, but was paused and unable to be completed, preventing efficient gene expression.”
The study highlights the underappreciated role of disordered protein interactions as key orchestrators in gene expression and other complex biological functions. The findings also can contribute to a better understanding of diseases such as cancer, viral infections, neurodevelopmental disorders and potentially other conditions in which these factors are disrupted. TNDs and TIMs may represent important novel targets for improved treatments for these conditions.
- Kateřina Čermáková, Jonas Demeulemeester, Vanda Lux, Monika Nedomová, Seth R. Goldman, Eric A. Smith, Pavel Srb, Rozálie Hexnerová, Milan Fábry, Marcela Mádlíková, Magdalena Hořejší. Jan De Rijck, Zeger Debyser, Karen Adelman, H. Courtney Hodges*, Václav Veverka*. A ubiquitous disordered protein interaction module orchestrates transcription elongation. Science 2021. https://doi.org/10.1126/science.abe2913