RT Journal Article
SR Electronic
T1 Widespread Increase in Enhancer—Promoter Interactions during Developmental Enhancer Activation in Mammals
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.18.516017
DO 10.1101/2022.11.18.516017
A1 Zhuoxin Chen
A1 Valentina Snetkova
A1 Grace Bower
A1 Sandra Jacinto
A1 Benjamin Clock
A1 Iros Barozzi
A1 Brandon J. Mannion
A1 Ana Alcaina-Caro
A1 Javier Lopez-Rios
A1 Diane E. Dickel
A1 Axel Visel
A1 Len A. Pennacchio
A1 Evgeny Z. Kvon
YR 2022
UL http://biorxiv.org/content/early/2022/11/20/2022.11.18.516017.abstract
AB Remote enhancers are thought to interact with their target promoters via physical proximity, yet the importance of this proximity for enhancer function remains unclear. Although some enhancer–promoter loops are cell-type-specific, others are stable across tissues or even display reduced physical proximity upon activation. A major challenge is that relatively few enhancers are functionally characterized in vivo, making it difficult to draw generalized conclusions about enhancer–promoter looping during developmental gene activation. Here, we investigate the 3D conformation of enhancers during mammalian development by generating high-resolution tissue-resolved contact maps for nearly a thousand mammalian enhancers with known in vivo activities in ten murine embryonic tissues. We performed enhancer knockouts in mice, which validated newly identified enhancer–promoter chromatin interactions. The majority of enhancers display tissue-specific 3D conformations, and both enhancer–promoter and enhancer–enhancer interactions are significantly stronger upon enhancer activation in vivo. Less than 14% of enhancer–promoter interactions form stably across tissues; however, corresponding enhancers still display highly-tissue-specific activities indicating that their activity is uncoupled from a chromatin interaction with promoters. We find that these invariant interactions form in the absence of the enhancer and are mediated by adjacent CTCF binding. We also identified putative in vivo target genes for enhancers linked to congenital malformations, neurodevelopmental disorders, and autism, demonstrating the utility of our dataset for understanding human congenital disorders. Our results highlight the general significance of enhancer–promoter physical proximity for developmental gene activation in mammals.Competing Interest StatementThe authors have declared no competing interest.