Fibroblast growth factors (FGFs) prime the limb specific Shh enhancer for chromatin changes that balance histone acetylation mediated by E26 transformation-specific (ETS) factors

As an animal embryo develops, specific genes need to be switched on and off at the right time and place to ensure that the embryo’s tissues and organs form properly. Proteins called transcription factors control the activity of individual genes by binding to regions of DNA known as enhancers. Changes in the way DNA is packaged inside cells can affect the ability of transcription factors to access the enhancers, and therefore also influence when particular genes are switched on or off. Sonic hedgehog (or Shh for short) is a gene that helps to control various aspects of development including the formation of the limbs and brain. The limb forms from a structure in the embryo referred to as the limb bud. An enhancer called ZRS regulates the precise position within the limb bud where the Shh gene is active in a region designated as the “zone of polarizing activity”. Yet, it was not known how the enhancer is controlled to ensure this pattern is achieved. Peluso et al. investigated the events that lead to ZRS becoming active in mice embryos. The experiments show that the ZRS enhancer exists in three different states in cells across the limb bud: poised, active and inactive. The enhancer is poised in a broad region of the limb bud in cells that are potentially able to switch on the Shh gene. Proteins called fibroblast growth factors drive the enhancer to enter this poised state by altering the way the DNA containing the enhancer is packaged in the cell. Specific transcription factors are able to bind to the poised enhancer and it is the balance between these different transcription factors that activates the enhancer in the zone of polarizing activity. Furthermore in the region of the limb bud where the fibroblast growth factors are not present the ZRS is inactive. These findings show that fibroblast growth factors, in combination with other changes to the ZRS enhancer, restrict the area in which the enhancer is active to a particular region of the limb bud. Differences in enhancer elements are known to underlie a range of inherited characteristics and may influence whether an individual develops many common diseases. In the future, investigating how cells control the activity of enhancers may provide clues to identifying new targets for drugs to treat some of these diseases.