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The study was led by Mikko Taipale, associate professor of molecular genetics at the Donnelly Center for Cell and Biomolecular Research at the Temerty School of Medicine, with Anne-Claude Kingra, a senior investigator at the Lunenfeld-Tanenbaum Institute.
Anne-Claude Gingras)
.
The research was spearheaded by Taipale graduate student Nader Alerasool, who defended his doctoral thesis last month — just a day after the study was published online in the journal Molecular Cell , and ahead of this week.
published in print
.
In this article, the researchers describe the first unbiased proteome-scale study that increased the number of known transcriptional activators from a handful to approximately 250
.
They also determined how these proteins combine with other cellular mechanisms to turn on genes, and how dysregulation of the proteins contributes to cancer
"This study is a classic fishing, and we don't know what we're going to find," said Taipale, Canada Research Chair in Functional Proteomics and Proteostasis
.
"Grant reviewers generally disapprove of non-hypothesis-driven research, but that's the beauty of proteomics
"We now have a better understanding of which proteins are strong activators
.
We can start to understand how they activate transcription
To find the activator, the researchers tested most of the 20,000 human proteins for their ability to activate gene expression in human cells
.
Many activators are transcription factors (TFs), which bind directly to DNA and turn on their target genes, while others are accessory proteins or cofactors that bind TFs and together activate their target genes
They also found that highly similar transcription factors can talk to different cofactors, which explains why two transcription factors with essentially the same DNA-binding specificity can trigger different gene expression programs
.
"These activators are not activators in all contexts
.
It may be because they activate gene X, but may actually repress gene Y.
Transcriptional activation occurs through the interaction of so-called transcriptional activation domains, which are present in transcription factors, with activators
.
Since the activation domain sequence is not conserved, it cannot be precisely determined computationally
For this reason, the team cut 75 activators into pieces and tested each piece for its ability to activate transcription
.
They identified about 40 activation domains with this method
They also used AlphaFold, a revolutionary bioinformatic tool for predicting protein structures, to find the interface between TFs and their activators
.
Although AlphaFold wasn't originally designed to predict protein-protein interactions, this unexpected function was one of Taipale's highlights
"This was almost impossible to do computationally before," Taipale said
.
While many of the proteins identified were novel, some were previously detected in tumors where a TF and its accessory protein were permanently linked in an oncogenic fusion protein that ultimately activated the wrong gene
.
Piecing together the puzzle of how TFs interact with different activators could be an important step toward tailoring treatments
.
A challenge in therapeutic development is that transcription factors are not amenable to targeting with small-molecule drugs
.
"Transcription factors are difficult to target because they typically don't have drug pockets, but many coactivators are enzymes, which means they have pockets that can be targeted," Taipale said
.
For example, when you have a cancer in which transcription factors are associated with coactivators The fusion of the activator, you know the coactivator that the transcription factor interacts with, and you can target that coactivator to stop the cell from proliferating
.
"
Nader Alerasool, He Leng, Zhen-Yuan Lin, Anne-Claude Gingras, Mikko Taipale.
Identification and functional characterization of transcriptional activators in human cells .
Molecular Cell , 2022; 82 (3): 677
