Bioengineering experts at the Ecole Polytechnique Fédérale de Lausanne have discovered how to predict the efficiency with which transcription factors (TFs) locate the sites they need to bind to in order to regulate gene expression.
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The finding could help researchers determine which TFs are the most efficient at driving changes in gene expression patterns and influencing cell fate.
Gene transcription is the first step required for proteins to be made and TFs are the proteins that regulate this process. They work by scanning DNA and binding to specific sequences that will “switch” genes “on“ or “off.”
As well as binding to specific DNA regions, transcription factors are also known to bind non-specifically to any random DNA sequences. This non-specific binding can optimize the efficiency at which TFs home in on their specific binding sites, by enabling them to slide along the DNA.
However, scientists do not yet understand why the many hundreds of TFs in humans differ in their ability to locate those specific binding sites.
Now, David Suter and colleagues have found that the answer lies in their ability to bind to “mitotic” chromosomes.
By using photobleaching and single molecule imaging to study 501 TFs in a mouse model, the team found that mitotic chromosome binding could predict the movement of TFs in the nucleus and the efficiency with which they locate their binding sites.
Further studies combining these experiments with whole-genome TF mapping showed which TFs had the strongest ability to bind non-specifically to DNA.
Those TFs associated with mitotic chromosomes, moved slowly in the nucleus and were particularly efficient at locating the sites they need to bind to in order to regulate gene expression.
Transcription factors differ largely in their ability to scan the genome to find their specific binding sites, and these differences can be predicted by simply looking at how much they bind to mitotic chromosomes.”
David Suter, Lead Researcher
"Transcription factors that are the most efficient in searching the genome could be able to drive broad changes in gene expression patterns even when expressed at low concentrations and can therefore be particularly important for cell fate decision processes."