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Why point mutations in a general transcription factor are associated with specific forms of human malignancies has been a major question in cancer biology. Enhancers are DNA regulatory elements that can be transcribed and are key regulators of tissue-specific gene expression in development; their malfunction through point mutations in either regulatory elements or factors modulating enhancer-promoter communication could result in development problems. Indeed, recent genome-wide studies in the cataloging of somatic mutations in cancer have identified mutations in intergenic sequences encoding regulatory elements and in specific transcription factors that function in enhancer-promoter communication. This Keystone Symposia meeting will review recent reports in this regard and discuss the concept of enhancer malfunction in the misregulation of gene expression in development and in disease pathogenesis. This meeting is being held jointly with Noncoding RNAs in Health and Disease.