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Study Finds Tandem Repeats Can Influence Yeast Transcription

NEW YORK (GenomeWeb News) – The presence of tandem DNA repeats in Saccharomyces cerevisiae promoters influences the expression of genes regulated by those promoters, new research suggests — and may offer an evolutionary advantage that helps cells adjust their gene expression in response to environmental changes.

An international team of researchers mapped the location of tandem repeats or, TRs, in the S. cerevisiae genome and looked at the effect that these repeats had on gene expression in this organism. They found that the repeats were often found in nucleosome-free regions of gene promoters, affecting the expression of genes under the control of these promoters. The work, appearing in today's issue of Science, suggests that altering the number of repeat units in TRs may be used to regulate gene expression in cells.

"Variations in repeat length result in changes in expression and local nucleosome positioning," senior author Kevin Verstrepen, a researcher affiliated with Harvard University and the Katholieke Universiteit Leuven in Belgium, and his co-authors wrote. "Tandem repeats are variable elements in promoters that may facilitate evolutionary tuning of gene expression by affecting local chromatin structure."

Tandem repeats are stretches of repeating DNA sequences positioned next to one another head-to-toe. These TRs frequently mutate to acquire variable numbers of repeat units. While TRs were once considered non-functional, research indicates that repeats in protein coding genes may have functional roles, potentially increasing the ability to evolve, the authors noted.

"At first sight, it may seem unlikely that this stutter-DNA has any biological function," lead author Marcelo Vinces, a post-doctoral researcher in Verstrepen's lab, said in a statement. "On the other hand, it seems hard to believe that nature would foster such a wasteful system."

For the latest study, the team started by mapping the repeats in the genome of the yeast strain S288C. They found that TRs frequently fell within yeast promoters: roughly a quarter of promoters evaluated contained at least one TR.

And the number of repeat units in various TRs frequently differed from one yeast strain to the next. When the researchers sequenced 33 randomly selected TR-containing yeast promoters from seven S. cerevisiae strains, they found that 25 showed variable numbers of repeat units in at least one of the strains.

The team's subsequent analyses suggested that genes controlled by TR-containing promoters can adapt their transcriptional activity more quickly than other genes.

When they altered the number of TR repeat units in the promoters of three different yeast genes, the researchers found that increasing the number of repeat units in TR also ramped up gene expression — but only to a point. Once the number of repeats exceeded the optimal number, gene expression plummeted.

TR-containing promoters also appeared to help yeast alter their gene expression in response to specific conditions in the lab. The researchers' selection experiments suggest that promoter TRs containing about 13 repeat units had maximal gene expression.

Subsequent experiments suggested that both TR-related sequence and structure in promoters influenced gene expression. TRs were typically located some 200 base pairs upstream of a gene's translational start codon in areas lacking nucleosomes.

"Although several molecular mechanisms may underlie the effect promoter TRs have on gene expression, our data indicate that repeat-dependent changes in DNA sequence and chromatin structure play a role," Verstrepen and his co-authors wrote.

Overall, the authors suggested, such results may point to a general role for TRs in regulating gene expression and responding to environmental pressures. Since TR distribution in humans seems to be similar to that in yeast, they also speculated that TRs in promoters may contribute to transcriptional adaptation in other organisms as well.

"Our results presented here are consistent with a role for TRs as ubiquitous and adjustable 'evolutionary tuning knobs' for transcription that mediate rapid evolution of gene expression," the authors wrote. "Genes that respond to changing environmental conditions would be particularly suited for such variable genetic elements."

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