Researchers at the University of Toronto have created a best-in-class functional catalog of proteins that activate gene expression. This affects the personalized treatment of cancer and other diseases that occur when the wrong gene is switched on.
Also known as a transcriptional activator due to its ability to induce Transcription of gene In RNA messages, these proteins are essential for the proper functioning of cells. However, little is known about these proteins, and it has not been clear until now how many activators are present in human cells.
The study was led by Mikko Taiparet, an associate professor of molecular genetics at the Donnelly Cell Biomolecular Research Center in Terence School of Medicine, in collaboration with Anne Claude Ginglas, a senior researcher at the Runenfeld Tanenbaum Institute in Sinai. .. Professor of Health Systems and Molecular Genetics at the University of Toronto.
This work was led by Nader Alerasool, a graduate student in Taiparet who defended his PhD.Last month’s paper — the day after the study was published online in the journal Molecular cellAnd prior to the publication of this week’s printed matter.
In the article, researchers describe the first unbiased proteome-scale study that expanded the number of known transcriptional activators from a handful to about 250. It has also established a way for these proteins to bind to other cellular mechanisms to turn on genes, and for protein misregulation, which can lead to cancer.
“This study was a classic fishing expedition where we didn’t know what we were trying to find,” said Taiparet, chair of the Canadian Research Committee on Functional Proteomics and Proteostasis. “Grant reviewers usually frown on non-hypothetical research, but that’s the beauty of proteomics. You can cast the net in an unbiased way, and you’ve found some interesting ones. rice field.
“Now we have a better understanding of which proteins are very powerful activators, and we can begin to understand how they activate transcription.”
To find activators, researchers tested the majority of 20,000 human proteins for their ability to activate gene expression in human cells.Many activators Transcription factor (TF) was a helper protein or cofactor that binds directly to DNA and turns on the target gene, while other proteins bind to TF and activate the target together.
They also discovered that very similar TFs can communicate with different cofactors and explained why two TFs with essentially the same DNA binding specificity can trigger different gene expression programs.
“These activators are not activators in all situations. They can be activated in gene X, but can actually be suppressed in gene Y,” says Taipale. ..
Transcriptional activation is caused by the interaction of activators with the so-called transactivation domains present in TF. The sequence of activation domains is not preserved and cannot be determined by computational methods.
Therefore, the team chopped 75 activators and tested each piece’s ability to activate transcription. They identified about 40 activation domains in this way.
They also found an interaction interface between TF and its activators using AlphaFold, an innovative bioinformatics tool developed for predicting protein structure. AlphaFold isn’t designed to predict protein-protein interactions, but this unexpected feature is for Taiplee, who said the software would be the standard tool for this type of research to find functional connections between proteins. It was the highlight of.
“Until now, it was almost impossible to do this by calculation,” said Taiparet.
Many of the identified proteins are novel, but some of them were previously detected in tumors in which TF and its helper proteins are permanently bound by carcinogenic fusion. protein It activates the wrong gene.
Combining the puzzles of how TF interacts with different activators can be a major step towards tailored therapy. One challenge in therapeutic development was that TF was not suitable for targeting with small molecule drugs.
“Transcription factors are very difficult to target because they often do not have drug-discoverable pockets, but many co-operators.Activator It is an enzyme and means that it has pockets that can be targeted. For example, if you have a cancer fusion of a transcription factor and a coactivator and you understand the coactivator with which the transcription factor interacts, you may be able to target the coactivator and stop cell proliferation. ”
Nader Alerasool et al, Identification and functional characterization of transcriptional activators in human cells, Molecular cell (2022). DOI: 10.1016 / j.molcel.2021.12.008
University of Toronto
Quote: The researchers found the largest catalog of gene activators obtained on February 9, 2022 from https: //phys.org/news/2022-02-reveal-largest-gene.html (February 2022). 9th) revealed
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Researchers reveal the largest catalog of gene activators
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