We are interested in chromatin structure and its role in the repression and activation of genes; in the modulation of chromatin structure and function by relatively abundant accessory proteins; and in the structures of relevant protein-DNA complexes. We adopt a multidisciplinary approach (molecular biology, protein chemistry, NMR spectroscopy and other biophysical methods).
Particular areas of study include:
The unusual, extra, ‘intrinsically unstructured’ GII domain of the yeast linker histone Hho1p folds, in 250 mM sodium phosphate, into a structure very similar to that of the stably folded homologous GI domain. Structures determined by NMR spectroscopy (Ali et al., 2004).
The fundamental level of chromatin structure, the nucleosome filament, and its folding into higher-order structure. We are especially interested in the interactions of histone H1, which plays a structural role and may also be involved in regulation of the activity of certain genes. An intriguing and distinctive candidate H1 (Hho1p) in yeast which was revealed by the genome sequence is under active investigation (Ali et al., 2004).
An architectural and chaperone role for HMGB1 (green) in facilitation of transcription factor binding (left fork) and assembly of nucleoprotein complexes (right fork) (Thomas and Travers, 2001).
The abundant chromosomal proteins HMGB1 and 2 (high-mobility group proteins 1 and 2), which bend linear DNA and bind preferentially to bent and distorted DNA through their “HMG boxes” (Thomas and Travers, 2001). We are currently investigating, inter alia, the means by which these “architectural proteins” facilitate the assembly of nucleoprotein complexes containing sequence-specific proteins; the interaction of tandem “HMG boxes” with DNA; and the interaction of HMGB1 with chromatin.
The relationship between DNA methylation and repressed chromatin, and in particular the role and interactions of the methyl cytosine binding protein MeCP2, which has distinct methyl CpG-binding and transcriptional repression domains, as well as other regions of unknown function.
Lab members
Laura Cato, Jenifer Clark, Frederick Northrop, Lara Osmotherly, Alexandria Richart, John Rowell, Katherine Stott
References
Thomas, J.O. & Travers, A.A. (2001) HMG1 and 2 and related “architectural” DNA-binding proteins. Trends Biochem. Sci. 26, 167-174.
Drewell, R.A., Goddard, C.J., Thomas, J.O. & Surani, M.A. (2002) Methylation-dependent silencing of the imprinted H19 gene by MeCP2. Nucleic Acids Res. 30, 1139-1144.
Ali,T., Coles, P., Stevens, T.J., Stott, K. & J. O. Thomas (2004) Two homologous domains of similar structure but different stability in the yeast linker histone, Hho1p. J. Mol. Biol. 338, 139-148.