Entangled and non-modular enhancer sequences producing independent spatial activities

Sci Adv. 2024 Nov 22;10(47):eadr9856. doi: 10.1126/sciadv.adr9856. Epub 2024 Nov 20.

Abstract

The modularity of transcriptional enhancers is central to our understanding of morphological evolution, allowing specific changes to a gene expression pattern component, without affecting others. Enhancer modularity refers to physically separated stretches of regulatory sequence producing discrete spatiotemporal transcriptional activity. This concept stems from assays that test the sufficiency of a DNA segment to drive spatial reporter expression resembling that of the corresponding gene. Focusing on spatial patterns, it overlooks quantitative aspects of gene expression, underestimating the regulatory sequence actually required to reach full endogenous expression levels. Here, we show that five regulatory activities of the gene yellow in Drosophila, classically described as modular, result from extensively overlapping sequences, with broadly distributed regulatory information. Nevertheless, the independent regulatory activities of these entangled enhancers appear to be nucleated by specific segments that we called enhancer cores. Our work calls for a reappraisal of enhancer definition and properties, as well as of the consequences on regulatory evolution.

MeSH terms

  • Animals
  • Drosophila / genetics
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation

Substances

  • Drosophila Proteins