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September 26, 2017

Gene Expression Controlled by Nano Soccer Balls

  • To understand which set pieces lead to protein expression on the genomic soccer pitch, follow the bouncing nano soccer ball, a cluster of transcription factors that can slip between strands of DNA. In these plays, goals are scored when nano soccer balls reach gene promoter regions, switching them “on” or “off,” activating or repressing gene expression.

    Certain transcription factors, scientists based at the University of York have observed, do not roam the genome individually, as single molecules. Instead, they operate together, in relatively tight formation. In fact, they form ball-like clusters of around six to nine molecules of roughly 30 nm in diameter—roughly 10 million times smaller than regulation-size soccer balls.

    Because the nano soccer balls are so small, they could be glimpsed only by special means: single-molecule fluorescence microscopy. Using this super-resolution technique, a team of scientists led by the University of York’s Mark C. Leake, Ph.D., observed a green fluorescent protein–tagged transcription factor called Mig1 as it roamed within Saccharomyces cerevisiae yeast cells, the same type of yeast cells utilized in baking and brewing beer.

    "Our ability to see inside living cells, one molecule at a time, is simply breathtaking,” said Prof. Leake. "We had no idea that we would discover that transcription factors operated in this clustered way. The textbooks all suggested that single molecules were used to switch genes on and off, not these crazy nano [soccer] balls that we observed."

    Details of the scientists’ work appeared August 25 in the journal eLife, in an article entitled, “Transcription Factor Clusters Regulate Genes in Eukaryotic Cells.” The article describes how the scientists combined their microscopy observations and computer models of chromosomal structural dynamics to arrive at an unexpected finding: The Mig1 functional component that binds to promoter targets operates as a cluster of transcription factor molecules with stoichiometries of about six to nine molecules.

    “Our novel discovery of factor clustering has a clear functional role in facilitating factors finding their binding sites through intersegment transfer, as borne out by simulations of multivalent factors," wrote the article's authors. "This addresses a long-standing question of how transcription factors efficiently find their targets.”

    The authors added that the clustering they found also functions to reduce off-rates from targets compared to simpler monomer binding. This effect, the authors suggested, could improve robustness against false-positive detection of extracellular chemical signals.

    The discovery of these nano soccer balls may help researchers understand more about the basic ways in which genes operate. In addition, it may provide important insights into human health problems associated with a range of different genetic disorders, including cancer.

    The authors of the current study noted that in previous studies, simulations showed that intersegmental transfer between sections of nuclear DNA was essential for factors to find their binding sites within physiologically relevant timescales. They also cited single-molecule studies of p53 and TetR in human cancer cells that have also suggested a role for nonspecific (i.e., sequence independent) transcription factor searching along the DNA. These studies, however, left unanswered the question of how transcription factors find their targets in the genome so efficiently.

    Prof. Leake’s team indicated that the clustering process described in the current study could reflect an ingenious strategy that cells use to speed transcription factors to their target genes.

    "We found out that the size of these nano [soccer] balls is a remarkably close match to the gaps between DNA when it is scrunched up inside a cell,” explained Prof. Leake. “As the DNA inside a nucleus is really squeezed in, you get little gaps between separate strands of DNA which are like the mesh in a fishing net. The size of this mesh is really close to the size of the nano [soccer] balls we see.

    "This means that nano [soccer] balls can roll along segments of DNA but then hop to another nearby segment. This allows the nano [soccer] ball to find the specific gene it controls much more quickly than if no nano hopping was possible. In other words, cells can respond as quickly as possible to signals from the outside, which is an enormous advantage in the fight for survival."

    This new research may help provide insights into human health problems associated with a range of different genetic disorders. The next stages will be to extend this research into more complicated types of cells than yeast—and ultimately into human cells.

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