Pioneer factors play a critical role in differentiation by generating chromatin accessibility and by activating enhancers. As differentiation progress, additional tissue-specific transcription factors bind these enhancers thus generating a stable and robust regulatory network that is thought to be resistant to the loss of any specific transcription factor. I found that pioneer factors are continuously guarding enhancer activity throughout adult life thus maintaining tissue integrity. An exception to this is DNA hypomethylation at these sites that are programmed by pioneer factors in embryonic development and are not dependent on the continuous presence of pioneer factors in the adult tissue. These findings distinguish between cellular components that enhance stability versus those that enable plasticity.