Pleiotropy in enhancer function is encoded through diverse genetic architectures

Abstract

Developmental genes can have complex c/s-regulatory regions, with multiple enhancers scattered across stretches of DNA spanning tens or hundreds of kilobases. Early work revealed remarkable modularity of enhancers, where distinct regions of DNA, bound by combinations of transcription factors, drive gene expression in defined spatio-temporal domains. Nevertheless, a few reports have shown that enhancer function may be required in multiple developmental stages, implying that regulatory elements can be pleiotropic. In these cases, it is not clear whether the pleiotropic enhancers employ the same transcription factor binding sites to drive expression at multiple developmental stages or whether enhancers function as chromatin scaffolds, where independent sets of transcription factor binding sites act at different stages. In this work we have studied the activity of the enhancers of the shavenbaby gene throughout D. melanogaster development. We found that all seven shavenbaby enhancers drive gene expression in multiple tissues and developmental stages at varying levels of redundancy. We have explored how this pleiotropy is encoded in two of these enhancers. In one enhancer, the same transcription factor binding sites contribute to embryonic and pupal expression, whereas for a second enhancer, these roles are largely encoded by distinct transcription factor binding sites. Our data suggest that enhancer pleiotropy might be a common feature of c/s-regulatory regions of developmental genes and that this pleiotropy can be encoded through multiple genetic architectures.

Mutational scans reveal differential evolvability ofDrosophilapromoters and enhancers

“…The differential constraints observed in different cis-regulatory elements can help us predict where evolutionarily relevant substitutions could occur within a locus. They also support the previous findings that the evolution of svb consists of multiple small-effect substitutions throughout the locus in different Drosophila species (Frankel et al 2011;Preger-Ben Noon et al 2018). In the future, mutational scans by allele replacement at the endogenous loci will provide further insights into the fitness landscape of regulatory elements in a developmental context, paralleling those in microorganisms (Metzger et al 2015;Venkataram et al 2016) and cell lines (Sanjana et al 2016).…”

“…We focused our analyses on the regulatory sequences of shavenbaby (svb), a gene that encodes an essential regulator of trichome development in Drosophila. The evolution of the svb regulatory regions has been extensively studied due to contributions to phenotyic evolution across many Drosophila species (Sucena and Stern 2000;Frankel et al 2011;Crocker et al 2015;Preger-Ben Noon et al 2018). Through these works, seven transcriptional enhancers have been characterized for svb; each integrates information from multiple patterning networks giving rise to the overall expression of svb across the embryo (Fig.…”

Shavenbaby protein isoforms orchestrate the self-renewalversusdifferentiation ofDrosophilaintestinal stem cells

“…Although svb enhancers were delineated for their embryonic activity, they harbor pleiotropic functions across the Drosophila life-cycle (Bohere et al, 2018;Preger-Ben Noon et al, 2018). At least three enhancers drive svb expression within the lineage of adult intestinal stem cells.…”