Super-enhancers include classical enhancers and facilitators to fully activate gene expression

Joseph W. Blayney, Helena Francis, Alexandra Rampasekova, Brendan Camellato, Leslie Mitchell, Rosa Stolper, Lucy Cornell, Christian Babbs, Jef D. Boeke, Douglas R. Higgs, Mira Kassouf

Research output: Contribution to journalArticlepeer-review

Abstract

Super-enhancers are compound regulatory elements that control expression of key cell identity genes. They recruit high levels of tissue-specific transcription factors and co-activators such as the Mediator complex and contact target gene promoters with high frequency. Most super-enhancers contain multiple constituent regulatory elements, but it is unclear whether these elements have distinct roles in activating target gene expression. Here, by rebuilding the endogenous multipartite α-globin super-enhancer, we show that it contains bioinformatically equivalent but functionally distinct element types: classical enhancers and facilitator elements. Facilitators have no intrinsic enhancer activity, yet in their absence, classical enhancers are unable to fully upregulate their target genes. Without facilitators, classical enhancers exhibit reduced Mediator recruitment, enhancer RNA transcription, and enhancer-promoter interactions. Facilitators are interchangeable but display functional hierarchy based on their position within a multipartite enhancer. Facilitators thus play an important role in potentiating the activity of classical enhancers and ensuring robust activation of target genes.

Original languageEnglish (US)
Pages (from-to)5826-5839.e18
JournalCell
Volume186
Issue number26
DOIs
StatePublished - Dec 21 2023

Keywords

  • alpha globin locus
  • cis-regulatory elements
  • enhancer cluster
  • enhancer cooperation
  • facilitators
  • gene expression
  • genome engineering
  • super-enhancers
  • synthetic genome
  • transcriptional regulation

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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