Dynamic interplay between enhancer-promoter topology and gene activity.

TitleDynamic interplay between enhancer-promoter topology and gene activity.
Publication TypeJournal Article
Year of Publication2018
AuthorsChen, H, Levo, M, Barinov, L, Fujioka, M, Jaynes, JB, Gregor, T
JournalNat Genet
Volume50
Issue9
Pagination1296-1303
Date Published2018 09
ISSN1546-1718
KeywordsAnimals, Chromatin, Drosophila, Enhancer Elements, Genetic, Female, Gene Editing, Gene Expression Regulation, Developmental, Humans, Male, Promoter Regions, Genetic, Transcription, Genetic, Transcriptional Activation
Abstract

<p>A long-standing question in gene regulation is how remote enhancers communicate with their target promoters, and specifically how chromatin topology dynamically relates to gene activation. Here, we combine genome editing and multi-color live imaging to simultaneously visualize physical enhancer-promoter interaction and transcription at the single-cell level in Drosophila embryos. By examining transcriptional activation of a reporter by the endogenous even-skipped enhancers, which are located 150 kb away, we identify three distinct topological conformation states and measure their transition kinetics. We show that sustained proximity of the enhancer to its target is required for activation. Transcription in turn affects the three-dimensional topology as it enhances the temporal stability of the proximal conformation and is associated with further spatial compaction. Furthermore, the facilitated long-range activation results in transcriptional competition at the locus, causing corresponding developmental defects. Our approach offers quantitative insight into the spatial and temporal determinants of long-range gene regulation and their implications for cellular fates.</p>

DOI10.1038/s41588-018-0175-z
Alternate JournalNat Genet
PubMed ID30038397
PubMed Central IDPMC6119122
Grant ListR01 GM097275 / GM / NIGMS NIH HHS / United States
R01 GM117458 / GM / NIGMS NIH HHS / United States
U01 DA047730 / DA / NIDA NIH HHS / United States
U01 EB021239 / EB / NIBIB NIH HHS / United States