Transcription imparts architecture, function and logic to enhancer units

Nat Genet. 2020 Oct;52(10):1067-1075. doi: 10.1038/s41588-020-0686-2. Epub 2020 Sep 21.

Abstract

Distal enhancers play pivotal roles in development and disease yet remain one of the least understood regulatory elements. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites are robust predictors of active enhancers with higher resolution than histone modifications. We show that active enhancer units are precisely delineated by active transcription start sites, validate that these boundaries are sufficient for capturing enhancer function, and confirm that core promoter sequences are necessary for this activity. We assay adjacent enhancers and find that their joint activity is often driven by the stronger unit within the cluster. Finally, we validate these results through functional dissection of a distal enhancer cluster using CRISPR-Cas9 deletions. In summary, definition of high-resolution enhancer boundaries enables deconvolution of complex regulatory loci into modular units.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Clustered Regularly Interspaced Short Palindromic Repeats / genetics
  • Enhancer Elements, Genetic / genetics*
  • Histone Code / genetics*
  • Humans
  • Promoter Regions, Genetic / genetics
  • Protein Processing, Post-Translational / genetics
  • Transcription Initiation Site*
  • Transcription Initiation, Genetic
  • Transcription, Genetic*