Enhancer-Promoter Entanglement Explains Their Transcriptional Interdependence

Authors

Anil K Panigrahi
David M Lonard
Bert W O'Malley

Publication Date

1-24-2023

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2216436120

PMID

36656865

PMCID

PMC9942820

Published Open-Access

no

Keywords

Humans, Enhancer Elements, Genetic, Promoter Regions, Genetic, RNA, RNA, Messenger, Transcriptional Activation, Transcription, Genetic, Gene Expression Regulation, transcription activation, enhancer–promoter contact, eRNA

Abstract

Enhancers not only activate target promoters to stimulate messenger RNA (mRNA) synthesis, but they themselves also undergo transcription to produce enhancer RNAs (eRNAs), the significance of which is not well understood. Transcription at the participating enhancer-promoter pair appears coordinated, but it is unclear why and how. Here, we employ cell-free transcription assays using constructs derived from the human GREB1 locus to demonstrate that transcription at an enhancer and its target promoter is interdependent. This interdependence is observable under conditions where direct enhancer-promoter contact (EPC) takes place. We demonstrate that transcription activation at a participating enhancer-promoter pair is dependent on i) the mutual availability of the enhancer and promoter, ii) the state of transcription at both the enhancer and promoter, iii) local abundance of both eRNA and mRNA, and iv) direct EPC. Our results suggest transcriptional interdependence between the enhancer and the promoter as the basis of their transcriptional concurrence and coordination throughout the genome. We propose a model where transcriptional concurrence, coordination and interdependence are possible if the participating enhancer and promoter are entangled in the form of EPC, reside in a proteinaceous bubble, and utilize shared transcriptional resources and regulatory inputs.

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