Research Overview

Fig 1: View down nucleosome dyad axis illustrating richness of intramolecular interactions to be understood.
DNA (red), H3 (yellow), H4 (blue), H2A (cyan), H2B (grey)

Fig 2: Alternative models for mechanism of nucleosome sliding. Twist defect diffusion (upper) and bulge diffusion (lower).

Chromatin is the substrate for processes occuring in eukaryotic cell nuclei via its role as the universal genome packaging state. The nucleosome is the fundamental repeating subunit of chromatin so it is unsurprising that the histone proteins in the nucleosome are highly conserved.

The design principles of nucleosome structure are not understood despite this importance and conservation. Our aim is to understand the chromatin structure-function relationship in molecular detail.

Nucleosomes are dynamic, not static 'tuna cans', and they can undergo specific transitions such as sliding or histone exchange which are essential for their function. This dynamic behaviour appears to be a directed process, so the histone protein core must enable specific flexibility. We are working to determine its molecular motions using recombinantly produced nucleosomes and a variety of biochemical and biophysical assays.

ATP-dependent chromatin remodelling complexes all contain Snf2 family proteins as molecular engines at their core. The complexes behave as classical enzymes to direct and accelerate the rate of nucleosome structural changes by translating the chemical energy of ATP hydrolysis into mechanical motion which is applied as force to the nucleosome. The outcome of this is almost certainly intertwined with nucleosome dynamics so we are studying the mechanism of ATP-dependent remodelling.