We are interested in chromatin structure and its modulation by accessory proteins that affect gene activation and repression. We adopt a multidisciplinary approach, using biochemical and biophysical methods including NMR spectroscopy. Of particular interest are proteins that stabilise chromatin structure and are associated with gene repression (histone H1, HP1, MeCP2), and HMGB1, which is associated with more open, active chromatin.
HMGB1 bends DNA through its two ‘HMG boxes’ and the highly acidic C-terminal tail lowers the affinity of the boxes for DNA. Recent work has elucidated the regulatory role of the tail, which tracks across the DNA-binding surfaces, bringing the boxes into close proximity in a dynamic compact assembly. Interaction of the boxes with DNA or transcription factors (such as p53; currently under study), or of the tail with other partners, requires competition of the box-tail interaction. The interaction of HMGB1 and H1 through their acidic and basic tails respectively, would increase the affinity of HMGB1 for DNA and lower the affinity of H1, providing a potential mechanism for replacement of H1 by HMGB1 at certain active promoters.
Current work on HP1 focusses on its interaction with histone H3, providing important insights into the structural and functional role of HP1.
Lab members: Piotr Gierszewski, Joyce Ratti, Katherine Stott and Andrew Travers (academic visitor)
1. Thomas, J.O. and Travers, A.A. (2001) HMG1 and 2 and related “architectural” DNA-binding proteins. Trends Biochem. Sci., 26, 167-174.
2. Watson, M., Stott, K. and Thomas, J.O. (2007) Mapping intramolecular interactions between domains in HMGB1 using a tail-truncation approach. J. Mol. Biol., 374, 1286-1297.
3. Cato, L., Stott, K., Watson, M. and Thomas, J. O. (2008) The interaction of HMGB1 and linker histones occurs through their acidic and basic tails. J. Mol. Biol., 384, 1262-1272.
4. Stott, K., Watson, M., Howe, F.S., Grossman, J.G. and Thomas, J.O. (2010) Tail-mediated collapse of HMGB1 is dynamic and occurs via differential binding of the acidic tail to the A and B domains. J. Mol. Biol., 403, 706–722.
5. Thomas, J.O. and Stott, K. (2012) H1 and HMGB1: modulators of chromatin structure. Biochem. Soc. Trans., 40, 341-346.
6. Richart, A.N., Brunner, C.I., Stott, K., Murzina, N.V. and Thomas, J.O. (2012) Characterization of chromoshadow domain-mediated binding of heterochromatin protein 1α (HP1α) to histone H3. J. Biol. Chem., 287, 18730-7.
7. Rowell, J.P., Simpson, K.L., Stott, K., Watson, M. and Thomas, J.O. (2012) HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 transactivation domain interaction, regulated by the acidic tail. Structure, 20, 2014-24.