Structural mechanism of genome acetylation and 3D folding

Recent chromosome capture experiments have revealed a hierarchical 3D organisation of the genome ranging from Topologically Associating Domains (TADs) to larger-scale active, euchromatic and inactive, heterochromatic compartments.

TADs arise through chromatin loop extrusion by cohesin/CTCF while compartments arise through epigenetic modification of the chromatin polymer.

It has long been known that dynamic histone acetylation switches between repressive and permissive chromatin, a key event in transcriptional activation.

We aim to capture cohesin in different structural states to understand how it is regulated and catalyses large-scale chromatin transactions.

We also aim to understand the molecular mechanism behind acetylation-dependent activation of chromatin a reaction that is critical for the establishment of active euchromatin and may contribute to genome compartmentalisation and enhancer-promoter interaction.

This proposal has the potential to transform our understanding the molecular mechanism behind two key reactions that contribute short- and long-range 3D genome architecture.

It is possible that both mechanisms are interconnected and provide unifying principles to explain gene regulation with broad implications for health and disease.