Understanding the remote control of gene transcription: lessons from the pluripotency gene Sox2

Sophisticated control of gene expression programs during development is brought about by enhancers, elements which can activate target promoters over large genomic distances. Despite great progress in identify and characterizing enhancers, it is still not clear how exactly they regulate transcription with such specificity. Chromatin conformation capture experiments suggest that enhancers physically contact their regulated genes via “looping” interactions, but recent microscopy experiments raise questions over this simple model. Using the pluripotency gene Sox2, and its embryonic stem cell-specific enhancer, the SCR, as a model locus, we have uncovered different aspects of the spatiotemporal regulation of gene expression. In the first case, we find a surprising decoupling between aspects of the enhancer that are responsible for “interactions” and those that are necessary for transcriptional activation. In the second case, when tracking the promoter and enhancer in living cells, we find that their inherent mobilities are specifically matched when the gene is being transcribed. Overall, these results are consistent with a model whereby transcription is spatially coordinated in specialized nuclear microenvironments to facilitate distal regulation.