TYC Highlight Seminar: Intranuclear phase separation, and its role in transcription and gene regulation

avide Marenduzzo, University of Edinburgh

The recording of the seminar can be found here

Abstract: Microscopy studies suggest that chromatin and its associated proteins often form phase separated droplets within the nucleus of eukaryotic organisms. I will describe some possible biophysical mechanisms underlying such intranuclear phase separation and microphase separation (arrested phase separation resulting in the formation of droplets of self-limiting size). I will also discuss potential functional roles of phase separation in transcription, as active and inactive clusters are normally spatially segregated. 

Specifically, I will show that multivalent chromatin binding mediates cooperative interactions between proteins which naturally leads to the creation of phase separated clusters (through what we call the “bridging-induced attraction”). Such clusters are strikingly similar to nuclear bodies and transcription factories found in side eukaryotic nuclei. The model also suggests a potential role of clustering for gene regulation, and it provides potential solutions to puzzles concerning the actions of enhancers, super-enhancers, and expression quantitative trait loci. I will then discuss how the model can be enhanced to include the recently discovered “loop extrusion” so that it can predict 3D chromatin structure genome-wide, and how it can be used to study the dynamics of chromatin transcription so that it can predict the effect of 3D structure on transcriptional activity in human cells.