Science: "Noisy" gene expression plays a key role in development!

In cell biology, an important process is the process by which stem cells are transformed into all other cells in the body.
This process is called differentiation
.

However, this process is not to increase the temperature, but to amplify the random fluctuations in the level of gene expression, that is, the opening or closing of genes in the cell
.

"Researchers have studied and described these fluctuations, or'noise' in gene expression, for decades," said Dr.
Leor Weinberger, director of the Cell Circuit Research Center at the Gladstone Institute.
It is not clear whether this noise is just an inevitable by-product of gene expression or whether it performs certain functions, which is generally believed
.

Now, according to a new study in Science, he and his team have discovered a pathway called discordant transcription through repair (DiThR, pronounced "dither").
The DiThR pathway seems to increase the noise of gene expression in stem cells.
, Enhance their differentiation ability
.

A new basic mechanism

The discovery of the DiThR pathway stems from the team's early research on HIV
.

"We have been solving the long-standing problem of HIV, that is, how to change the ability of HIV to lie in the patient's body for a long time.
We have found that changing the molecules that the virus expresses noise will also reduce the persistence of HIV
.

"When the same molecules work in stem cells, it is quite surprising, and trying to understand how these molecules work has become an exploration of basic biological mechanisms," said Dr.
Weinberger
.

Leor Weinberger

When a gene is activated or expressed, the information stored in the gene is used to make the substances necessary for the cell to function
.

Most genes switch between active and inactive states, on and off every few minutes or hours
.

While studying HIV, Weinberger's team discovered the existence of some molecules that can increase noise or switch the expression mechanism between active and inactive states, but strangely, they do not affect the average expression level
.

But how these noise-enhancing molecules can increase noise without changing the expression level is completely unknown
.

On a whim, the scientists examined what happens when noise-enhancing molecules are applied to embryonic stem cells without HIV
.

The team’s main finding is that the mechanism by which noise-enhancing molecules enhance noise involves the process of repairing DNA errors that may occur when genes are activated
.

"We found that Apex1 directly changes the shape of the DNA double helix, first hindering and then accelerating gene expression," said Ravi Desai, the first author of the study
.

The team showed that Apex1 is a key element of this new DiThR pathway, which increases the noise of the entire gene array in the genome
.

Ravi Desai

Make differentiation more effective

Next, because some noise-enhancing molecules are naturally found in stem cells, the research team analyzed how the newly discovered mechanism affects the transformation of stem cells into other cell types
.
They used noise-enhancing molecules and substances that promote differentiation into other types of cells to treat mouse embryonic stem cells
.

They found that the increased noise transmitted by DiThR allows stem cells to differentiate more efficiently, just like the Bunsen burner does on chemical reactions
.

More importantly, this mechanism also works in the opposite direction
.
It improves the efficiency of the process of turning differentiated cells back into pluripotent stem cells.
Pluripotent stem cells may become several different types of cells.
This discovery won Shinya Yamanaka the Nobel Prize in 2012
.

Desai said: "Our findings indicate that the DiThR pathway makes cells more sensitive to signals that guide their fate
.
This means that this mechanism may play a fundamental biological role in embryonic development
.
"

Looking ahead, the research team plans to further map out the various components of the DiThR pathway
.

Weinberger said: "Our goal now is to understand how DiThR is regulated and whether there are related noise control pathways
.
Ultimately, methods that use these pathways can greatly improve cell engineering and stem cell-based therapies
.
"

(Biocom)

Original title:

A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions