Hyperacetylated Chromatin Domains Mark Cell Type-Specific Genes and Suggest Distinct Modes of Enhancer Function

Stratification of enhancers by relative signal strength in ChIP-seq assays has resulted in the establishment of super-enhancers as a widespread and useful tool for identifying cell type-specific, highly expressed genes and associated pathways. We have examined a distinct method of stratification that focuses on peak breadth, termed “hyperacetylated chromatin domains” (HCDs), which classifies broad regions exhibiting histone modifications associated with gene activation. We find that this analysis serves to identify genes that are both more highly expressed and more closely aligned to cell identity than super-enhancer analysis does when applied to multiple datasets. Moreover, genetic manipulations of selected gene loci suggest that at least some enhancers located within HCDs work at least in part via a distinct mechanism involving the modulation of covalent histone modifications across domains, and that this activity can be imported into a heterologous gene locus. In addition, such genetic dissection reveals that the super-enhancer concept can obscure important functions of constituent elements.