Mechanisms of long-range gene control -- hints of a role for phase transition

Long-range enhancers - found as far away as 1 megabase from their target gene - are key in controlling precise spatial and temporal gene expression in mammals. In contrast to the 20,000 or so genes in our genome, there may be hundreds of thousands, or even millions, of enhancers. Deletion, translocation or point mutations can abrogate the function of these elements in Mendelian diseases associated with severe phenotypes. Moreover, the majority of human genetic variation associated with common disease and quantitative traits also map to enhancers. I will describe our work probing how high-order three-dimensional chromatin structure relates to how enhancers work from a distance. I will present data consistent with the popular chromatin-looping mechanism for enhancer action. However, using a synthetic biology approach, I will also present data inconsistent with a 'looping' mechanism at other enhancers and suggesting that poly (ADP- ribosylation)-mediated chromatin decompaction is linked to enhancer activation. These data will be placed in the context of recent models that implicate liquid de-mixing/phase transitions in chromatin-mediated gene regulation.