Increased enhancer-promoter interactions during developmental enhancer activation in mammals

Area of Science:

• Genomics
• Developmental Biology
• Epigenetics

Background:

• Remote enhancers are hypothesized to interact with target promoters through physical proximity, but the functional significance of this interaction is not fully understood.
• Understanding enhancer-promoter interactions is key to deciphering gene regulation during mammalian development.

Purpose of the Study:

• To investigate the three-dimensional (3D) conformation of enhancers during mammalian development.
• To determine the importance of physical proximity for enhancer function in vivo.

Main Methods:

• Generation of high-resolution, tissue-resolved contact maps for nearly a thousand enhancers with characterized in vivo activities in ten murine embryonic tissues.
• Analysis of enhancer-promoter and enhancer-enhancer interactions in the context of developmental gene activation.

Main Results:

• Sixty-one percent of developmental enhancers bypass neighboring genes, often marked by promoter CpG methylation.
• The majority of enhancers exhibit tissue-specific 3D conformations.
• Enhancer-promoter and enhancer-enhancer interactions increase moderately upon enhancer activation, with less than 14% forming stably across tissues.

Conclusions:

• Physical proximity between enhancers and promoters is generally important for developmental gene activation in mammals.
• Enhancer-promoter interactions are dynamic and often tissue-specific.
• Invariant enhancer-promoter interactions may be mediated by CTCF binding and form independently of enhancer presence.