Transient promoter interactions modulate developmental gene activation [CaptureC]
Transcriptional induction coincides with the formation of various chromatin topologies, including loss and gain of physical interactions between promoters and distal regulatory elements (DREs). Strong evidence supports that gene activation is accompanied by a general increase in promoter-enhancer interactions. However, it remains unclear how these topological changes are coordinated across time and space to collectively enable transcription. Here we combine chromatin conformation capture with profiling of histone modifications, RNA polymerase II and transcription during an embryonic stem cell differentiation time-course to determine how 3D genome restructuring is related to transcriptional transitions. Using this approach, our data identifies distinct topological alterations that are associated with the magnitude of transcriptional induction. We detect transiently formed interactions between gene promoters and DREs and demonstrate by genetic deletions that these DREs can contribute to the transcriptional induction of associated genes. Finally, by acutely depleting cohesin, we interfere with early transient promoter-enhancer interactions, and show that this impairs the activation of linked genes. Taken together, our study identifies typical topological alterations during gene activation, links them to the magnitude of transcriptional induction, and detects an uncharacterized type of transcriptional enhancers. Our data are compatible with a model where the type of topological pattern that a promoter displays during developmental transitions and the dynamics and magnitude of its transcriptional induction are interdependent. Overall design: For the time-course analysis of promoter differentiation mouse embryonic stem cells (E14) were differentiated using retinoic-acid treatment and samples were collected at 0, 2, 4, 6, 24, 48 and 72 hours of treatment in biological duplicates to conduct Capture-C. A total of four sets of view points were assessed (sets 1-3 deeply sequenced, set4 shallow sequencing). To assess how transient interactions are affected by cohesin depletion, mESCs with and without acute depletion of SCC1 were differentiated for four hours. Samples were collected in triplicates. To assess how interactions are affected by the absence of the transient DRE DRE.H5.100 samples were collected at 0, 24 and 72 hours.