What are super-enhancers?

Journal name:
Nature Genetics
Year published:
Published online


The term 'super-enhancer' has been used to describe groups of putative enhancers in close genomic proximity with unusually high levels of Mediator binding, as measured by chromatin immunoprecipitation and sequencing (ChIP-seq). Here we review the identification and composition of super-enhancers, describe links between super-enhancers, gene regulation and disease, and discuss the functional significance of enhancer clustering. We also provide our perspective regarding the proposition that super-enhancers are a regulatory entity conceptually distinct from what was known before the introduction of the term. Our opinion is that there is not yet strong evidence that super-enhancers are a novel paradigm in gene regulation and that use of the term in this context is not currently justified. However, the term likely identifies strong enhancers that exhibit behaviors consistent with previous models and concepts of transcriptional regulation. In this respect, the super-enhancer definition is useful in identifying regulatory elements likely to control genes important for cell type specification.

At a glance


  1. Defining super-enhancers.
    Figure 1: Defining super-enhancers.

    (a) Illustration of the three-step procedure to define super-enhancers. Step 1: enhancer loci are defined by calling peaks on ChIP-seq data for cell type–specific master transcription factors22. Step 2: enhancers within 12.5 kb of each other are combined into stitched enhancer regions. Both stitched enhancer regions and enhancers without partners within 12.5 kb are used in the next step to identify super-enhancers. Step 3: ChIP-seq signal for Med1 for each enhancer region (both stitched and single enhancers) is calculated. All enhancer regions are ranked along the x axis on the basis of the Med1 enrichment plotted on the y axis. Super-enhancers are defined as regions to the right of the inflection point of the resulting curve (highlighted in gray). (b) Table summarizing all factor combinations that have been used in steps 1 and 3 to define super-enhancers in different papers, demonstrating that super-enhancers can be defined in the absence of Med1 ChIP-seq data.

  2. Schematic of an experimental approach to characterizing super-enhancers.
    Figure 2: Schematic of an experimental approach to characterizing super-enhancers.

    Use of genome editing tools, such as the CRISPR-Cas9 system, provides a methodology to create a minimal targeted deletion to test the activity of specific putative enhancers within super-enhancer loci by assessing the consequences of genetic deletions on gene activity.


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  1. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.

    • Sebastian Pott &
    • Jason D Lieb

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