“Intranuclear phase separation, and its role in transcription and gene regulation”

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.

 

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