Project Reference: TRG27-BIO-KS1

Project title: Biophysical models of chromatin compaction

Project outline

In eukaryotic chromatin, linker histones (H1s) engage the nucleosomal fibre to organise the higher-order structures that are essential for proper gene regulation. H1 subtypes exchange during development, and are extensively post-translationally modified, directly affecting chromatin structure and activity. Our lab uses in vitro models to uncover how the structure and biophysical properties of chromatin are influenced by H1s and their modifiers. We have shown that the long, disordered C-terminal tail of H1 acts as a liquid-like ‘glue’ for chromatin, that is loosened by H1 phosphorylation [1,2]. At the sequence level, we find that the properties of individual linker histones are conferred by their amino acid 'grammar', which differs between their C-terminal tails, and we have arrived at a new H1 ‘condensation code’ [3].

Aims:

To expand the H1 condensation code to include the effect of various post-translational modifiers (e.g. kinases, poly-ADP ribosyl transferases) and exchange factors (e.g. histone chaperones) on H1-condensed chromatin. The precise details of the project can be tailored to the student’s interests within this area.

Objectives:

Reconstitute chromatin models or purify from a natural source; investigate the structural and material properties of the system; probe its responsiveness to condensing and decondensing agents.

Methodology:

Biochemistry and molecular biology; molecular biophysics (e.g. optical tweezers combined with confocal microscopy); structural methods (NMR, Cryo-EM/ET).

[1] Turner et al., Highly disordered histone H1-DNA model complexes and their condensates. PNAS, 115, (2018). https://doi.org/10.1073/pnas.1805943115

[2] Gibbs, E.B. & Kriwacki, R.W. Linker histones as liquid-like glue for chromatin

(Commentary on [1]). PNAS, 115, (2018). https://doi.org/10.1073/PNAS.1816936115

[3] Watson et al., A DNA condensation code for linker histones. PNAS, 121, (2024).

https://doi.org/10.1073/pnas.2409167121

Principal Supervisor

Dr Katherine Stott

Email address: ks123@cam.ac.uk

Department / Partner Institute: Biochemistry

Website: https://www.bioc.cam.ac.uk/research/faculty/katherine-stott

BBSRC strategic theme

Understanding the rules of life