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Dynamics and stability of covalent protein modifications

Final Report Summary - PROTMOD (Dynamics and stability of covalent protein modifications)

One of the major goals of post-genomic biological research is to understand the molecular basis and physiological role of covalent protein modifications. These post-translational modifications (PTMs) can regulate protein interactions and/or stability and thus trigger particular downstream responses. The best-characterised substrates for multisite PTMs are currently the histone proteins. It has been suggested that PTMs of histones constitute a so-called "histone code". Whilst it is still under discussion if the modifications form a true "code", it is now well established that changes of histone modifications are involved in the regulation of all genes in eukaryotic cells. Nonetheless the set of characterised histone modifications is far from complete and many modifications are awaiting identification.
Deciphering this "histone code" will be a key step in understanding nuclear processes. We are currently only beginning to comprehend the many implications of this epigenetic information for biology and diseases. The major challenges are now to functionally characterise new modifications, to understand how they are translated into changes in gene expression and in particular how their misregulation can lead to cellular transformation.
The aim of Protmod was to study and functionally characterise novel PTMs of histones, their impact on gene expression, chromatin function and development. However, the significance of studying post-translational modifications extends beyond the field of chromatin research, because changes in the modification patterns are likely to affect many -if not all- aspects of protein functions. Therefore apart from their role in chromatin function, it is important for us to use histones as a model system to understand how covalent modifications can regulate protein function.

Amongst the main contributions of my group based on Protmod are:
(i) We demonstrated a causative function for histone modifications and established modifications within the core of the nucleosome as major regulators of chromatin function (Daujat et al., 2009; Tropberger et al., 2013; Lange et al., 2013; Tropberger and Schneider, 2013; di Cerbo et al., 2014) addressing key questions about the causality of histone modifications. We have unravelled the role of these novel modifications in cellular proliferation, differentiation, reprogramming and development.
(ii) We have for the first time systematically studied and unravelled the function of linker histone H1 modifications. We showed e.g. that H1 phosphorylation has a role in regulating cell proliferation (Hergeth et al., 2011) and that H1 acetylation has a dual function in transcriptional activation (Kamierniarz et al., 2012).
(iii) We have established a novel focus on H1 variants and gained insights in the functional specificity of H1 variants and their functions. We integrated H1 variants into epigenomic maps by identifying their genome-wide distribution (Izzo et al., 2008; Izzo et al., 2013).

Thus Protmod has led to the identification and functional characterisation of novel PTMs and to significant new insights in the biological function of these new modifications and their mode of action.