Enhancer Activation by Transcription Factors and Underlying Mechanisms

Enhancers are classified into two classes based on various criteria. Class I enhancers participate primarily in finely tuned cell-specific regulation, as exemplified by the neural enhancers discussed in Chap. 9 . They are activated by simultaneous binding of transcription factors (TFs) to adjacent sites in the core sequence and are marked by moderate levels of H3K27ac modification. Class II enhancers are activated by the reiterated binding of the same TFs at multiple sites and are marked by high levels of H3K27ac modification. Class II enhancers are exemplified by enhancers in the SCR downstream of the Sox2 gene, as also discussed in Chap. 9 . Both classes of enhancers activate transcription similarly with low selectivity toward the promoters.The genomic loci broadly covered by high-level H3K27ac modification were once dubbed "Super-enhancers," implying that they are densely packed enhancers with superpowers in gene regulation. However, marking with H3K27ac modification does not predict the enhancer activity of a sequence; a "Super enhancer" region includes a few ordinary Class II enhancers. Currently, the most reliable criterion for enhancer prediction is cross-species sequence conservation.The mechanism by which transcription factors find and stay on the target enhancer site remains elusive. Results from two approaches, single-molecule live imaging and kinetic analysis using FRAP, are discussed.