Nat Genet, co-auth. M-C. Gambetta

Enhancer-promoter interactions become more instructive in the transition from cell-fate specification to tissue differentiation

Tim Pollex 1 2Adam Rabinowitz 1Maria Cristina Gambetta 1 3Raquel Marco-Ferreres 1Rebecca R Viales 1Aleksander Jankowski 1 4Christoph Schaub 1Eileen E M Furlong 5

Affiliations expand

. 2024 Apr;56(4):686-696.

 doi: 10.1038/s41588-024-01678-x. Epub 2024 Mar 11.


To regulate expression, enhancers must come in proximity to their target gene. However, the relationship between the timing of enhancer-promoter (E-P) proximity and activity remains unclear, with examples of uncoupled, anticorrelated and correlated interactions. To assess this, we selected 600 characterized enhancers or promoters with tissue-specific activity in Drosophila embryos and performed Capture-C in FACS-purified myogenic or neurogenic cells during specification and tissue differentiation. This enabled direct comparison between E-P proximity and activity transitioning from OFF-to-ON and ON-to-OFF states across developmental conditions. This showed remarkably similar E-P topologies between specified muscle and neuronal cells, which are uncoupled from activity. During tissue differentiation, many new distal interactions emerge where changes in E-P proximity reflect changes in activity. The mode of E-P regulation therefore appears to change as embryogenesis proceeds, from largely permissive topologies during cell-fate specification to more instructive regulation during terminal tissue differentiation, when E-P proximity is coupled to activation.