Researchers reveal largest catalog of gene activators

Date:
February 11, 2022
Source:
University of Toronto
Summary:
Researchers have created a functional catalog of proteins that
activate gene expression, with implications for tailored therapy
for cancer and other diseases that occur when wrong genes are
switched on.



FULL STORY ==========================================================================
Also known as transcriptional activators for their ability to induce transcription of genes into RNA messages, these proteins are essential for
the cells to function properly. Yet little is known about these proteins,
and it wasn't clear how many activators there might be in human cells --
until now.


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The research was led by Mikko Taipale, an associate professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research
at the Temerty Faculty of Medicine, in collaboration with Anne-Claude
Gingras, a senior investigator at the Lunenfeld-Tanenbaum Research
Institute, Sinai Health System and professor of molecular genetics at
U of T.

The work was spearheaded by Taipale's graduate student Nader Alerasool,
who defended his PhD thesis last month -- a day after the study was
published online in the journal Molecular Cell, and ahead of print
publication this week.

In the article, the researchers describe the first unbiased proteome
scale study that has expanded the number of known transcriptional
activators from a handful to around 250. They have also established how
these proteins combine with other cellular machineries to turn genes on,
and how protein misregulation can lead to cancer.

"This study was a classic fishing expedition where we did not know what
we were going to find," said Taipale, who holds Canada Research Chair in Functional Proteomics and Protein Homeostasis. "Grant reviewers typically
frown upon research that is not hypothesis driven, but that's the beauty
of proteomics. It allows you to cast a net in an unbiased way, and we
have found some interesting stuff.

"We now have a better understanding of which proteins are very strong activators. And we can begin to understand the mechanisms by which they activate transcription." To find the activators, the researchers tested
the majority of 20,000 human proteins for their ability to activate gene expression in human cells. Many activators were transcription factors
(TFs), which directly bind DNA and turn on their target genes, whereas
others were helper proteins, or co-factors, that bind TFs and activate
their targets together.



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They also found that TFs that are highly similar can talk to different co- factors, explaining why two TFs with essentially identical DNA binding specificities can trigger distinct gene expression programs.

"These activators are not activators in all contexts. It could be that
in a gene X they activate, but in gene Y they might actually repress,"
Taipale said.

Transcriptional activation occurs through the interaction of the
so-called transactivation domains, which are present in the TFs, with
the activators.

Since the sequences of activation domains are not conserved, they can't
be pinpointed by computational methods.

For that reason, the team resorted to chopping up 75 activators
into pieces and tested the ability of each piece to activate
transcription. They identified around 40 activation domains this way.

They also used AlphaFold, a revolutionary bioinformatic tool developed for
the prediction of protein structures, to find the interaction interfaces between the TFs and their activators. Although AlphaFold was not designed
to predict protein-protein interactions, this unexpected feature was a highlight for Taipale, who said the software will become the standard
tool for these kinds of studies to find functional connections between proteins.



========================================================================== "This has been previously nearly impossible to do computationally,"
Taipale said.

While many of the identified proteins are novel, some of them were
previously detected in tumours in which a TF and its helper protein
are permanently joined in an oncogenic fusion protein which ends up
activating the wrong genes.

Piecing together the puzzle of how TFs interact with different activators
could be a major step towards tailored therapy. One challenge in
therapeutics development has been that TFs are not amenable to targeting
by small-molecule drugs.

"Transcription factors are really hard to target because they often
don't have druggable pockets, but many of the co-activators are enzymes
which means they have pockets that can be targeted," said Taipale. "For example, when you have a cancer fusion of the transcription factor to the co-activator and you understand the co-activator that the transcription
factor interacts with, you may be able to target the co-activator to
halt cell proliferation." The research was supported by the Donnelly
Centre startup funds, a Canada Foundation for Innovation John R. Evans
Leaders Fund grant and the Canadian Institutes of Health Research.

========================================================================== Story Source: Materials provided by University_of_Toronto. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. 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 DOI: 10.1016/j.molcel.2021.12.008 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220211080617.htm

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