Action at a distance in transcriptional regulation*

The three-dimensional organization of chromatin in the cell nucleus has profound consequences on the functional state of the system in terms of gene activity. However, the exact cause and consequence of this organization with respect to transcriptional activity remains elusive. For example, there is evidence that protein binding to specific sites along DNA called enhancers can activate the reading out of genetic information of genes separated by tens or hundreds of thousands of base pairs along the DNA. How does this separation translate into actual distances in physical space at the moment of gene activation? An approach based on high-resolution multi-color imaging is presented to discriminate the specificity of various DNA elements in establishing and maintaining discrete chromosomal configurations at the single cell level. Specifically, targeting a locus with multiple enhancers driving expression in distinct spatial domains in a developing embryo, we simultaneously measure the position of regulatory elements inside and outside their domains of control, and establish specific links between spatial enhancer-promoter configurations and expression domains. Results are presented that suggest a tight relationship between gene activity and specific spatial chromatin arrangements. In particular transcription causes a local decompaction in conjunction with sustained enhancer-specific proximity. The magnitude of this proximity is too large, however, to imply that there is direct contact between the activating enhancer and the active promoter. How then can information about gene activity travel from the enhancer to the promoter across several hundred nanometer through a liquid physical space?