Sharing enhancers for a different outcome

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The diverse structures that constitute the body of an animal must arise from a single genome, but how the genome is regulated in order to specify equivalent cell types in diverse body parts is unknown. A new study of appendage development in fruitflies now shows that, contrary to what might be expected, at any one time in development the same regulatory enhancers are available in equivalent tissue types in different appendages. Thus, the authors propose that it is the master regulators in these tissues that determine the distinct structures.

The authors sought to determine how enhancers regulate appendage development in Drosophila melanogaster by carrying out formaldehyde-assisted isolation of regulatory elements followed by high-throughput sequencing (FAIRE–seq) on dissected precursors of thoracic appendages. This technique identifies open chromatin and hence available enhancers. The appendages are comprised of similar cell types but are structurally different. Therefore, the authors expected to find that, at early developmental stages, different enhancers would be available to specify the structural differences. Surprisingly, in three different appendage precursors — those of the wing, haltere and leg — the FAIRE–seq patterns were all similar. Furthermore, the FAIRE–seq profiles of the developing wing, haltere and leg change coordinately over time. So what specifies the different identities of the appendages?

Further investigation revealed that enhancer availability varied at loci that encode key developmental regulators such as Ultrabithorax. Thus, the authors propose that tissues at any one developmental stage have the same available enhancers but that the choice of enhancer activity is made by master regulators, which affects the precise timing and the level of activity of the enhancers and thus dictates the appendage-specific differences.

Further evidence for this master regulator hypothesis came from examining the FAIRE–seq patterns in more detail. The authors showed that some enhancers were consistently accessible in the wing and leg despite the fact that the genes that are regulated by these enhancers are differentially expressed between the two appendages.

These results also have implications for evolution. The finding that morphologically distinct structures share a set of available enhancers suggests that all appendages are derived from a common ancestral 'appendage regulatory network'.

Finally, an unresolved issue is the degree to which the reported open chromatin profiles vary among the cell types within a tissue. This may be addressed using emerging single-cell techniques.


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Stower, H. Sharing enhancers for a different outcome. Nat Rev Genet 15, 2 (2014).

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