Transcriptional condensates coordinate the heat shock response

Transcriptional condensates, membrane-less compartments within the nucleus of eukaryotic cells, have been found to play a critical role in activating genes in response to environmental stress. While previous research had shown their importance in mammalian cells, a recent research demonstrated their presence in yeast as well. This suggests that transcriptional condensates are an ancient and conserved tool used by eukaryotic cells to promote high-level gene expression for over a billion years.

The implications of this discovery extend beyond fundamental biology and into medicine. The heat shock response, which is regulated by transcriptional condensates, is an essential process for human health. In response to high temperatures, cells turn on molecular chaperones that help maintain protein stability. However, cancer cells can hijack this process to help mutated proteins stay folded, and neurodegenerative diseases such as Alzheimer’s disease are characterized by a lack of molecular chaperones that leads to excessive protein aggregation.

Recently, researchers at the University of Chicago led by Professor David Pincus  conducted a study and found that transcriptional condensates, the same machinery that mammalian cells use to promote cellular differentiation, are also essential for activating genes in yeast in response to environmental stress. The study, published in Molecular Cell, suggests that transcriptional condensates are a conserved tool that eukaryotic cells have been using for over a billion years to promote high-level gene expression. These findings not only help explain how cells respond dynamically to environmental cues but also have implications for understanding human diseases such as cancer and neurodegeneration.

Transcriptional condensates are membrane-less compartments within the nucleus of the cell that concentrate transcriptional machinery, allowing for rapid and high-level transcription of specific critical genes under certain conditions, such as specifying a cell lineage or responding to stress. In response to high environmental temperatures, cells turn on molecular chaperones, which help maintain protein stability. This heat shock response is hijacked by cancer cells to help mutated proteins stay folded and gets broken down in neurodegenerative diseases such as Alzheimer’s disease, where a lack of molecular chaperones leads to excessive protein aggregation.

The study extends existing research on transcriptional condensates in mammalian cells into yeast and their heat shock response. The researchers used a series of genetic mutations to demonstrate that yeast cells use the same mechanism to coordinate the heat shock response. This is the first time these condensates have been seen in a non-eukaryotic species, demonstrating that these structures are very ancient, dating back to a very early common ancestor and conserved across species.

Previous research in mammalian cells had shown that eukaryotes use these membrane-less compartments to drive high-level gene expression by creating hubs where relevant DNA sequences and transcriptional activators can collect and drive transcription. The current study provides evidence that these genes are driven together in 3D space by these biomechanical condensates to facilitate gene transcription.

The researchers say that this mechanism likely dates back to the dawn of life, and cells have been using it to promote high-level gene expression for over a billion years. The study also establishes a new model for the yeast heat shock response, demonstrating how genes come together to drive high levels of transcription activity during the stress response. The key gene, Hsf1, collects and concentrates these genes together in these transcriptional condensates and brings in other genes to drive this transcription.

As a next step, the team plans to further investigate the mechanism of transcriptional condensates, seeking to better understand how the condensates form and how they drive the 3D reorganization of the genome. Ultimately, better understanding the mechanism and its biological significance could pave the way for new medical treatments, if researchers are able to develop drugs that modulate the formation and activity of the condensates directly.

Understanding the mechanism of transcriptional condensates could pave the way for new medical treatments. Researchers could develop drugs that modulate the formation and activity of the condensates directly, potentially preventing the hijacking of the heat shock response by cancer cells or enhancing the response in neurodegenerative diseases. Additionally, better understanding how the condensates form and drive the 3D reorganization of the genome could lead to new insights into gene regulation and cellular differentiation, which could have implications for a variety of diseases.

Furthermore, the discovery that transcriptional condensates are an ancient and conserved tool used by eukaryotic cells highlights the importance of studying fundamental biological processes. By understanding how cells have evolved to respond dynamically to environmental cues, researchers can gain new insights into the mechanisms that underlie human health and disease.