Structural and functional analysis of chromatin compaction

Chromatin compaction is a key process in the cell, modulating many biological reactions such as gene expression, chromatin attachment to the nuclear pore, telomere stability and DNA repair. Although the underlying mechanisms are not well known, it is thought that the binding of chromatin regulators restricts access of a variety of factors to DNA. The role of factors involved in chromatin compaction is linked to diseases such as cancer and neurological disorders. Currently, work in the Speck lab has been focussing on elucidating the structural changes during chromatin compaction and their consequences. This PhD project will aim to fully elucidate the molecular mechanisms of chromatin compaction by a specific set of chromatin regulators using cryo-EM analysis of reconstituted chromatin, and to deduce how this process is modulated by linker histones. Biophysical techniques will be employed to investigate the dynamics of chromatin and its compacted form. A cohort of disease-associated mutants of chromatin compaction factors will be assessed in order to investigate how these mutants impact on chromatin architecture. During the course of the PhD project various DNA sequences will be used as a template for chromatin assembly, including sequences found in heterochromatic regions of the human genome, or sequences related to disease. This project will help to provide a structural understanding of chromatin and describe in particular the conformational landscape of hetero-chromatin.