This "super enhancer" has been used for more than 1 billion years! The latest study in the journal Cell has discovered the mechanisms that allow multicellular formation

A new study from the University of Chicago has found that the mechanisms by which mammalian cells drive cell differentiation also play a key role
in activating yeast genes in response to environmental stressors.
The findings, published Nov.
17 in the journal Molecular Cell, show that these machines, known as transcriptional agglutes, are ancient, conserved tools that have been used by eukaryotic cells to boost high-level gene expression for more than 1 billion years
.
The findings not only help better explain how cells dynamically respond to environmental cues, but also help understand human diseases
such as cancer and neurodegeneration.

This study extends existing research on transcriptional condensates in mammalian cells to yeast and its heat shock response—how cells respond
to heat.
Dr.
David Pincus, assistant professor of molecular genetics and cell biology at the University of Chicago, said: "The heat shock response has a long
history.
" This reaction existed long before humans appeared, and even before yeast appeared! It predates the division of prokaryotes and eukaryotes, so it is a very basic and important cellular response
.
”

Transcriptional agglutination is the aggregation and concentration of transcriptional mechanisms within the nucleus of membrane-free compartments—almost like organelles, but lacking membranes—that allow rapid and high-level transcription of specific key genes under specific conditions, such as the designation of a cell lineage or the response to
stress.

In response to a high-temperature environment, cells initiate chaperones, which help maintain protein stability
.
This heat shock response can be hijacked by cancer cells to help the mutated protein remain folded
.
In neurodegenerative diseases such as Alzheimer's disease, this response is broken down because the lack of chaperones leads to excessive aggregation of
proteins.

"We know that this heat shock response is important for human health, and we know that the relevant genes are induced
in large quantities," Pincus said.
"But it's
not clear how cells coordinate this response to drive gene expression.
"

Previous studies of mammalian cells have shown that eukaryotes use these membraneless compartments to drive high levels of gene expression by creating distribution centers where relevant DNA sequences and transcriptional activators can be collected and drive transcription
.
In the current study, the researchers used a series of genetic mutations to demonstrate that yeast cells use the same mechanism to coordinate the heat shock response
.

Surabhi Chowdhary, a postdoctoral scholar in the Pincus lab at the University of Chicago, said: "In our previous research, we saw that genes that are regulated in heat stress reactions converge and are activated
in 3D space.
" "This study provides evidence that these genes are driven together in 3D space by these biomechanical condensations to facilitate gene transcription
.
"

This is the first time these condenses have been found in non-eukaryotic species, suggesting that the structures are very ancient, dating back to a very early common ancestor, and remain conserved
between species.
"This means that cells have been doing this advanced gene expression for 1 billion years
," Pincus said.
"When these condensates form, they are not formed on a single gene, but have the ability to bring a bunch of genes together and activate them
at the same time.
"

The results also establish a new model
for yeast heat shock reaction.
"Until now, it was unclear how these genes clumped together to drive high levels of transcriptional activity in the stress response
.
Now we know that the key gene Hsf1 works in a special way by collecting and concentrating these genes in these transcriptional aggregates and introducing other genes to drive this transcription.

”

The researchers say this mechanism may be traceable back to the origin of
life.
"You must have heard of primordial soup, where life begins in these concentrated layers of nutrients
," Pincus said.
Think of these condensates as 'primordial super enhancers'
.
This mechanism may have been part of the blast cell stress response, which was later used to drive cell differentiation, paving the way
for multicellular life.
”

As a next step, the team plans to further investigate the mechanisms of transcriptional condensation, trying to better understand how condensation is formed and how they drive the genome's 3D reorganization
.
Ultimately, if researchers can develop drugs that directly regulate condensate formation and activity, a better understanding of its mechanisms and their biological significance will pave the way
for new medical approaches.

"It's
exciting to know that cells don't let anything go by their fate," Pincus says.
We think of a cell as a loose bag of enzymes, but everything is organized in space and time
.
It's like we take the hood off the hood of a car and watch the engine turn and see these basic evolutionary processes at work
.
If cells can't cope with changes in the environment, we're all screwed
.
It's a beautiful thing
.
”

Original:

Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response