Enhancer biology in normal and malignant cells. The center of the figure shows how, in normal tissue, cell-type-specific transcription factors (TFs) bind to enhancer elements to drive expression of target cell identity genes, while enhancers utilized in alternative cell lineages are poised or silenced. (a) Enhancer (E1) repression in the course of cancer development through either acquisition of DNA methylation or chromatin compaction blocking TF binding. (b) Genetic alterations in an enhancer (E1), altering its normal function through either blocking TF binding or inducing the binding of a new TF. (c) Enhancer (E2) activation in the course of cancer development through epigenetic changes, resulting in chromatin openness favorable to TF binding and target gene expression. (d) Genetic alterations resulting in the activation of an enhancer (E2) normally inactive in normal cells. eRNA, enhancer RNA; LF, chromatin looping factors; P, promoter; PolII, RNA polymerase II.