Reverse-Engineering a Transcriptional Enhancer: A Case Study in Drosophila
Publication: Tissue Engineering Part A
Volume 14, Issue Number 9
Abstract
Enhancers, or cis-regulatory elements, are the principal determinants of spatiotemporal patterning of gene expression. For reasons of clinical and research utility, it is desirable to build customized enhancers that drive novel gene expression patterns, but currently, we largely rely on “found” genomic elements. Synthetic enhancers, assembled from transcription factor binding sites taken from natural signal-regulated enhancers, generally fail to behave like their wild-type counterparts when placed in transgenic animals, suggesting that important aspects of enhancer function are still unexplored. As a step toward the creation of a truly synthetic regulatory element, we have undertaken an extensive structure–function study of an enhancer of the Drosophila decapentaplegic (dpp) gene that drives expression in the developing visceral mesoderm (VM). Although considerable past efforts have been made to dissect the dppVM enhancer, transgenic experiments presented here indicate that its activity cannot be explained by the known regulators alone. dppVM contains multiple, previously uncharacterized, regulatory sites, some of which exhibit functional redundancy. The results presented here suggest that even the best-studied enhancers must be further dissected before they can be fully understood, and before faithful synthetic elements based on them can be created. Implications for developmental genetics, mathematical modeling, and therapeutic applications are discussed.
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Published In
Tissue Engineering Part A
Volume 14 • Issue Number 9 • September 2008
Pages: 1549 - 1559
PubMed: 18687053
Copyright
Copyright 2008, Mary Ann Liebert, Inc.
History
Published online: 7 September 2008
Published in print: September 2008
Published ahead of print: 8 August 2008
Accepted: 12 June 2008
Received: 1 February 2008
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