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, and use it to classify broad regions exhibiting histone modifications associated with gene activation as “hyperacetylated chromatin domains” (HCDs). We find that application of this analysis to multiple datasets serves to identify genes that are both more highly expressed and more closely aligned to cell identity than “super-enhancer” analysis does. Moreover, genetic manipulations of selected gene loci suggest that at least some HCDs harbor enhancers that work by distinct mechanisms, and in turn reveal that the “super-enhancer” concept can obscure important functions of constituent elements. Overall design: ATAC-Seq of mouse proeyrthorblasts and ChIP-seq (H3K4Me1, H3K4Me2, H3K4Me3, H3K27Ac) analysis of mouse 14.5 fetal liver