Batting practice in the genome
In the biochemical game of genetics, proteins were seen as either 'spectators' or 'players' in gene regulation. But that idea is changing. Researchers now find spectator proteins are actually at batting practice, gearing up for the big game.
Researchers discovered that proteins biochemically interact with thousands of regions in the genome in order to change its structure, but only a few actually play in the big game of turning genes on (or "expression" in gene parlance).
appear in the current issue of eLife.
"The previous thinking was that these proteins were wasting time and energy, like office workers spending time on Facebook. But they're actually more like baseball players at batting practice, warming up for the real thing - the actual gene switch."
David Arnosti PhD, Professor of Biochemistry, Director of Gene Expression in Development and Disease Initiative, Michigan State University
This discovery, made while examining gene switches in the Drosophila [or fruit fly], could lead to a better understanding of the DNA/protein complexes controlling gene expression. It even points to ways these elements may have evolved and could have major ramifications on human health, potentially in treating diseases such as Alzheimer's and cancers.
"Understanding gene control switches is important to understanding how humans work and our vulnerability to disease," Arnosti adds.
Arnosti's lab has developed a new method to directly trace the biochemical impact of a regulatory protein on the embryo. Their new observations suggest previous genome-wide studies may have mistaken "batting practice" for regulatory elements — a difference that impacts our understanding how genomic mutations may affect gene expression. "Batting" practice may also serve a long-term role.
"The process provides an evolutionary opportunity. 'Practice' elements can quickly change into the real thing, allowing gene networks to easily rewire when under evolutionary pressure. This changes our evaluation of active versus pseudo gene switches - our current approach is too simplistic."
David Arnosti PhD
Using fruit flies as a model system is a matter of convenience. Fruit flies have an overall genome typical in many animals. They are inexpensive, easy to manipulate with their short life cycles.
"Fruit flies have the same molecular circuitry as humans, going back to ancient mechanisms more than 500 million years old," Arnosti adds.
Metazoan transcriptional repressors regulate chromatin through diverse histone modifications. Contributions of individual factors to the chromatin landscape in development is difficult to establish, as global surveys reflect multiple changes in regulators. Therefore, we studied the conserved Hairy/Enhancer of Split family repressor Hairy, analyzing histone marks and gene expression in Drosophila embryos. This long-range repressor mediates histone acetylation and methylation in large blocks, with highly context-specific effects on target genes. Most strikingly, Hairy exhibits biochemical activity on many loci that are uncoupled to changes in gene expression. Rather than representing inert binding sites, as suggested for many eukaryotic factors, many regions are targeted errantly by Hairy to modify the chromatin landscape. Our findings emphasize that identification of active cis-regulatory elements must extend beyond the survey of prototypical chromatin marks. We speculate that this errant activity may provide a path for creation of new regulatory elements, facilitating the evolution of novel transcriptional circuits. - See more at: http://elifesciences.org/content/4/e06394#sthash.2TSuLAGl.dpuf
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