Phenotypic robustness conferred by apparently redundant transcriptional enhancers

Abstract

Transcriptional enhancers are segments of regulatory DNA located some distance from the coding region of a gene. Sometimes, several of them can serve apparently redundant functions — driving the production of a gene's messenger RNA at the same stage and place in embryonic development. Frankel et al. now demonstrate in Drosophila that such 'redundant' enhancers (in this case, two enhancers of the embryo-patterning gene shavenbaby), by contributing higher overall levels of transcription, ensure robustness of phenotypes against both genetic and environmental perturbations; for example, mutations in other genes or temperature changes that would otherwise lead to aberrant development. Transcriptional enhancers are segments of regulatory DNA located some distance from the coding region of a gene, and several of them may sometimes serve apparently redundant functions. These authors demonstrate in Drosophila that such 'redundant' enhancers, by contributing higher overall levels of transcription, ensure robustness of phenotypes against both genetic and environmental perturbations, for example mutations in other genes or temperature changes that would otherwise lead to aberrant development. Genes include cis-regulatory regions that contain transcriptional enhancers. Recent reports have shown that developmental genes often possess multiple discrete enhancer modules that drive transcription in similar spatio-temporal patterns1,2,3,4: primary enhancers located near the basal promoter and secondary, or ‘shadow’, enhancers located at more remote positions. It has been proposed that the seemingly redundant activity of primary and secondary enhancers contributes to phenotypic robustness1,5. We tested this hypothesis by generating a deficiency that removes two newly discovered enhancers of shavenbaby (svb, a transcript of the ovo locus), a gene encoding a transcription factor that directs development of Drosophila larval trichomes6. At optimal temperatures for embryonic development, this deficiency causes minor defects in trichome patterning. In embryos that develop at both low and high extreme temperatures, however, absence of these secondary enhancers leads to extensive loss of trichomes. These temperature-dependent defects can be rescued by a transgene carrying a secondary enhancer driving transcription of the svb cDNA. Finally, removal of one copy of wingless, a gene required for normal trichome patterning7, causes a similar loss of trichomes only in flies lacking the secondary enhancers. These results support the hypothesis that secondary enhancers contribute to phenotypic robustness in the face of environmental and genetic variability.