All the genome’s a stage, and all the regulatory proteins mere players—or not. Some regulatory proteins just go through the motions, like understudies learning lines they may never perform for real. Such proteins, it now appears, may do more than strut and fret their hour upon the genomic stage, they may also move genomic props and change the genomic scenery, however ineffectually.

All this activity, warns a researcher team based at Michigan State University, can fool scientists into thinking they are witnessing an actual performance. This research team, led by David N. Arnosti, Ph.D., adds that understudy proteins may not be simply wasting time and energy. Instead, they may be keeping themselves ready for their big break. One day, if evolutionary pressures reshuffle the genome’s regulatory cast, a struggling understudy protein may quickly step into a starring role.

To better understand how DNA/protein complexes control gene expression, the Michigan State researchers examined gene switches in Drosophila embryos. In particular, the researchers studied the conserved Hairy/Enhancer of Split family repressor Hairy, analyzing histone marks and gene expression.

Previous studies suggested that while regulatory factors such as Hairy may bind to many genomic sites, these factors often do so without effect. And so, many binding sites were thought to be inert. According to Dr. Arnosti’s team, supposedly inert binding sites are subject to modification. It’s just that the modifications—the addition or removal of histone tags—may not be accompanied to any changes in gene expression.

Hairy, which mediates histone acetylation and methylation in large blocks, is known to reduce gene expression. However, Hairy-mediated changes in the vicinity of certain genes are ignored, while in other cases, Hairy introduces chromatin changes to genes that are already silent. Such superfluous modifications, say the Michigan State researchers, are instances of “errant targeting.”

The researchers detailed their work August 25 in the journal eLife, in an article entitled, “Genome-wide errant targeting by Hairy.”

“Most strikingly, Hairy exhibits biochemical activity on many loci that are uncoupled to changes in gene expression,” wrote the authors. “Rather than representing inert binding sites, as suggested for many eukaryotic factors, many regions are targeted errantly by Hairy to modify the chromatin landscape.”

The authors assert that their findings indicate that the identification of active regulatory elements must extend beyond the survey of prototypical chromatin marks. That is, genomics studies that label regulatory sites solely by changes to their chromatin modifications may be fooled by the apparent activity of errantly targeted sites. Such activity may be irrelevant to gene regulation.

The authors add, however, that errant activity may “provide a path for creation of new regulatory elements, facilitating the evolution of novel transcriptional circuits.”

“This process provides an evolutionary opportunity, where 'practice' elements may quickly change to the real thing, allowing genetic networks to be readily rewired under the selection of evolutionary pressure,” explained Dr. Arnosti. “This changes in a major way evaluations of active and pseudo gene switches—the current approach is too simplistic.”

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