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.
Highlights
The transcriptional control of gene expression in eukaryotes is governed by cis-regulatory elements, known as enhancers, that integrate cell-type and temporal information by binding combinations of transcription factors
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. 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
Summary
The transcriptional control of gene expression in eukaryotes is governed by cis-regulatory elements, known as enhancers, that integrate cell-type and temporal information by binding combinations of transcription factors. Genes that exhibit complex expression patterns are typically controlled by multiple cis-regulatory elements, some of which have overlapping, partially redundant activities [1,2,3,4]. Feedback autoregulation is a well-known motif in transcriptional networks [8], mechanisms that might be used to tune expression levels are not well understood. This problem is challenging for genes that have multiple, partially redundant regulatory inputs. Ubx negative autoregulation Somewhat paradoxically, transient ectopic expression of Ubx, induced either by heat shock or Gal4-mediated expression, resulted in Ubx loss-of-function transfomations that can be visualized both in the adult (as haltere to wing transformations; [11]) and in 3rd instar haltere imaginal discs (as groups of cells that showed a reduction or complete loss of Ubx protein) [12]
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