My research has aimed at exploring at a molecular level how transcription factors and chromatin remodeling proteins work, alone or in complex, to define an active or repressed gene transcription state. Because of the complexity of the system, we have studied these molecular machines at a range of spatial resolutions with a number of techniques, such as X-ray crystallography, NMR, Cryo-electron microscopy, SAXS, and well as biochemical and biophysical techniques.

Stemming from my previous work on RNA translocases and helicases, I have developed a specific interest in chromatin remodeling ATPases. These molecules contain a catalytic ATPase/DNA-translocase domain and flanking regions that bind nucleosomal epitopes. In the last few years, we dissected the roles of the chromatin targeting and motor domains of chromatin remodeler CHD4 and demonstrated that their activities are allosterically regulated. We are further investigating CHD4 by a combination of Cryo-EM and solution studies of subdomains by NMR.

A second theme of research has focused on a multi-protein transcription factor complex including Stem Cell Leukaemia protein (SCL) and regulatory protein LMO2. This complex critically regulates haematopoiesis and induces T-ALL Leukaemia. My objectives were to understand the molecular mechanisms driving complex formation and DNA interactions. In the last few years, we solved the structure of LMO2, which lead us to propose a model for its mechanism of action. Importantly we then solved the structure of SCL:E47:LMO2:LDB1LID bound to DNA. Dissection of the complex interactions combined with mammalian two-hybrid binding studies and in vivo studies in zebrafish embryos, revealed complex synergies between components of the complex their co-factors and DNA targets and deepened our understanding of how tissue-specific gene expression programs might be regulated.

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