Regulation of Ubx Expression by Epigenetic Enhancer Silencing in Response to Ubx Levels and Genetic Variation

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Abstract
For gene products that must be present in cells at defined concentrations, expression levels must be tightly controlled to ensure robustness against environmental, genetic, and developmental noise. By studying the regulation of the concentration-sensitive Drosophila melanogaster Hox gene Ultrabithorax (Ubx), we found that Ubx enhancer activities respond to both increases in Ubx levels and genetic background. Large, transient increases in Ubx levels are capable of silencing all enhancer input into Ubx transcription, resulting in the complete silencing of this gene. Small increases in Ubx levels, brought about by duplications of the Ubx locus, cause sporadic silencing of subsets of Ubx enhancers. Ubx enhancer silencing can also be induced by outcrossing laboratory stocks to D. melanogaster strains established from wild flies from around the world. These results suggest that enhancer activities are not rigidly determined, but instead are sensitive to genetic background. Together, these findings suggest that enhancer silencing may be used to maintain gene product levels within the correct range in response to natural genetic variation. Gene expression is generally governed by cis-regulatory elements, also called enhancers. For genes whose expression levels must be tightly controlled, enhancer activities must be tightly regulated. In this work, we show that enhancers that control the expression of the Hox gene Ultrabithorax (Ubx) in Drosophila are regulated by a negative autoregulatory feedback mechanism. Negative autoregulation can be triggered by less than a two-fold increase in Ubx levels or by varying the genetic background. Together, these data reveal that enhancer activities are not always hardwired, but instead may be sensitive to genetic and environmental variation and, in some cases, to the amount of gene product they regulate. The finding that enhancers are sensitive to genetic background suggests that the regulation of gene expression is more plastic than previously thought and has important implications for how transcription is controlled in vivo.