A team led by researchers from Baylor College of Medicine and the Czech Academy of Sciences has discovered a new piece of the puzzle of how gene expression is orchestrated. Published in the journal Science, the results reveal a new mechanism that coordinates the assembly of components inside cells that control gene expression. The mechanism is not only essential for normal cell function, but it has also been implicated in cancer, neurodegeneration and HIV infection, and may suggest new ways of treating these conditions.
“Most of the previous studies have focused on particular cellular components that turn genes on or off completely,” said co-corresponding author Dr H. Courtney Hodges, assistant professor of molecular and cellular biology and at the Center for Precision Environmental Health in Baylor. “Our work reveals a new perspective: proteins that regulate the level of gene expression can also work collectively to fine-tune expression levels in many different settings. We have identified a mechanism that brings these proteins together and plays a widespread role in health and disease. “
In previous work with colleagues at KU Leuven in Belgium, the team had studied protein interactions in leukemia and HIV infection, in particular those mediated by protein regions called TFIIS N-terminal domains (TND) . In the present study, the researchers extended the study of TNDs and found them in many other proteins.
“Everywhere we looked, we found these domains, particularly in the machinery that regulates transcription elongation, one of the first steps in gene expression in all human cells. Transcription lengthening is a complex cellular process that involves many different proteins working together, ”said first author Dr. Katerina Cermakova, postdoctoral fellow at the Hodges Lab. “We found that TNDs are the most enriched structural element of all the transcriptional lengthening factors. Once you research them, you find that all of the important protein complexes involved in the lengthening of transcription have a TND or bind to a protein that has one. “
Previous work has suggested to researchers that TNDs act as a docking platform for other protein regions, especially for small portions of unstructured proteins known as TND interaction motifs (TIMs).
Proteins have segments with a well-organized 3-D structure, but many also have segments that do not have such an organization. These disordered or unstructured regions are often functional.
“One remarkable thing about these unstructured regions is their unusual behavior as molecules,” said co-corresponding author Dr Vaclav Veverka, structural biologist and group leader at the Institute of Organic Chemistry and biochemistry of the Czech Academy of Sciences (IOCB Prague). “Imagine a TIM as a string loose at one end and moving as if it were blown away by a hurricane. But when she finds her TND partner, the string curls up and clings very tightly to the TND to keep it close. The researchers show that this attachment plays an important role in the early stages of gene expression.
“We first determined that TNDs and TIMs bind in ‘test tube’ type experiments, but it was really exciting to see that they bind to each other in living cells, thus validating the relevance of our observations in living systems, “said Cermakova. “We have also determined that TND-TIM interactions are very specific.”
“I was surprised to see that IWS1, a protein that was previously thought to be a secondary player in the transcriptional elongation machinery, acts as a central organizer of these factors,” said Hodges, a member of the Dan L Duncan Comprehensive Cancer Center at Baylor.
“We discovered that IWS1 uses specific TND-TIM interactions to coordinate the activities of many transcriptional regulators at the same time, making it appear like a conductor in a symphony that keeps all factors working in harmony and in close proximity. “said Veverka.
The team also explored the consequences of the disruption of 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 stage of gene expression started, but was interrupted and could not be completed, preventing efficient gene expression.”
The study highlights the underestimated role of disordered protein interactions as key orchestrators in gene expression and other complex biological functions. The findings may also contribute to a better understanding of diseases such as cancer, viral infections, neurodevelopmental disorders and potentially other conditions in which these factors are disturbed. TNDs and TIMs may represent important new targets for improving the treatment of these conditions.