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Collepardo_Wales_2017

Exploring the energy landscape of histone tail proteins: structural disorder, epigenetic effects, and DNA binding

 

Joint project: Dr. Rosana Collepardo and Prof. David Wales.

 

The three-dimensional organisation of DNA is one of the great marvels of physical biology. By winding around a special class of proteins known as histones, DNA manages to avoid entanglement, compresses enormously to fit inside tiny (6 μm) nuclei and, moreover, maintains exquisite control over the accessibility of its data. A set of chemical modifications that extend the genome, known as epigenetic marks, are responsible for this control. Unlike the DNA sequence, which is exactly the same in all our cells (e.g. liver, skin, brain), the distribution of epigenetic marks (epigenome) is different in each cell type. Epigenomes allow DNA sequences to be interpreted differently, generating diversity in cells and tissues. Increasing evidence suggests that epigenomes regulate gene function by directly transforming the nanostructure.

 

Deciphering how epigenetic marks govern the physiological form of the genome (chromatin) is critical for unravelling some of the most basic cellular functions, including transcription activation and gene silencing. Chromatin is the actual substrate for all DNA-directed processes, and thus changes in chromatin structure are intimately linked to gene regulation. Chromatin is formed by a sequence of DNA-protein particles (nucleosomes) joined by free DNA linker segments. The nucleosomes have evolved extraordinary charged and contoured surfaces, along with charged and flexible protruding ‘arms’, known as histone tails, that allow them to control the organization of the DNA inside chromatin with high precision.

 

This project aims to elucidate the mechanisms by which histone tail structural diversity is modulated and the implications for control of chromatin structure. This insight will be achieved through characterization of the energy landscapes for histone tails H4 and H3 using powerful new tools within the energy landscape framework. We have chosen these two tails because they are known to mediate the majority of internucleosome interactions. We will also investigate how binding to small DNA segments (which occurs within the chromatin context), and the presence of epigenetic modifications with strong effects on chromatin structure (e.g. acetylation and phosphorylation), transform the energy landscapes of such tails. This information will help us to understand the importance of protein structural disorder for the organization of the genome in three dimensions.