Chromatin structure and function
Genes, encoded in very long and fine strings of DNA, determine how organisms develop and function. In eukaryotes, the DNA is confined to the nucleus where it is wrapped into chromatin, which consists of many different proteins that package the genomic material. Many essential cellular processes like transcription, repair and duplication of the genome happen in the context of chromatin. Like a city, the nucleus is divided into different neighbourhoods, with quiet zones called heterochromatin, and centres of bustling activity called euchromatin. As organisms develop and cells assume more and more specialised roles in the body, each cell arranges its chromatin neighbourhoods in a way that supports the gene expression program corresponding to the cell’s function in the organism. Dysfunction of cellular programs and loss of genome organisation is at the heart of diseases ranging from viral infections to cancer and plays an important role in ageing.
In my group, we study chromatin structure and the macromolecular machines that are crucial for establishing and maintaining genomic neighbourhoods. We are particularly interested in understanding how chromatin is organised in 3D and how the heterochromatin machinery silences specific regions of the genome.
The basic repeating unit of chromatin is the nucleosome consisting of ~150 base pairs of DNA and four histone core proteins as well as a linker histone protein. Previous and current studies have shown that nucleosomes interact with each other to form higher-order chromatin structures, but where and how these interactions exactly occur on live genomes, and what their role is with respect to genome function remains poorly understood. We are developing methods to get at these questions using both in vitro model systems as well as the fission yeast model organism S. pombe, which is an excellent model for studying the formation and function of heterochromatin. Furthermore, using X-ray crystallography in conjunction with genetic and biochemical experiments we are studying the mechanistic aspects of large macromolecular machines that establish heterochromatin. Recently, we have contributed to understanding the nucleosome remodelling and deacetylation complex SHREC. This molecular assembly of proteins is responsible for silencing genes that are found in heterochromatic regions and we have established the molecular details of how the complex ties together its subunits. This understanding allows us now to focus on the question of how chromatin recruits and regulates SHREC in order to guide its gene silencing activity.
- Leopold K, Stirpe A, Schalch T. (2019) Transcriptional gene silencing requires dedicated interaction between HP1 protein Chp2 and chromatin remodeler Mit1. Genes Dev. 33(9-10):565-577.
- Ekundayo B, et al. (2017) 'Capturing structural heterogeneity in chromatin fibers.' J Mol Biol, vol. 429. Pp. 3031-3042.
- Job G, et al. (2016) 'SHREC Silences Heterochromatin via Distinct Remodeling and Deacetylation Modules.' Mol Cell, vol. 62. Pp. 207–221.
- Kuscu C, et al. (2014) 'CRL4-like Clr4 complex in Schizosaccharomyces pombe depends on an exposed surface of Dos1 for heterochromatin silencing.' Proc Natl Acad Sci USA, vol. 111. Pp. 1795–1800.
Luke Bailey, Alessandro Stirpe, Sarah Northall