Histone H3 lysine 27 acetylation-marked enhancer regions (H3K27ac enhancers)

H3K27ac-marked enhancer regions are distal regulatory elements in the genome characterized by the acetylation of lysine 27 on histone H3, a modification that distinguishes active enhancers from poised or inactive ones (Creyghton et al., 2010). These regions facilitate high levels of transcription by recruiting co-activators like p300/CBP and the Mediator complex, which bridge the enhancer to target gene promoters to initiate RNA polymerase II activity (Heintzman et al., 2009). In many diseases, particularly cancer, clusters of these enhancers known as super-enhancers drive the disproportionate expression of key oncogenes such as MYC, making them critical drivers of the malignant phenotype (Lovén et al., 2013). Because these regions are heavily occupied by reader proteins like BRD4, they have become focal points for epigenetic therapy using small molecules. Drugs such as BET inhibitors (e.g., OTX015) and p300/CBP inhibitors (e.g., A-485) work by disrupting the interaction between these enhancers and the transcriptional machinery, thereby suppressing oncogenic gene programs (Lasko et al., 2017). However, targeting these regions poses significant therapeutic challenges due to the potential for widespread disruption of normal gene expression and associated systemic toxicities (Hnisz et al., 2013).

Other names

Active enhancersH3K27ac-enriched regionsSuper-enhancersH3K27ac-marked regulatory elements

Inhibition of bromodomain-containing proteins (readers) or histone acetyltransferases (writers) to disrupt the assembly of transcriptional complexes at active enhancer sites.