Our research interests lie in the area of Structural and Computational Epigenetics, a new, fast growing field at the frontiers of modern Biology and translational medical research. In this context, our group studies the structure, dynamics and interactions of chromatin-associated proteins employing a wide spectrum of biophysical and computational techniques, such as NMR, Fluorescence and Circular Dichroism Spectroscopy, Molecular Dynamics and Molecular Modeling. Current Molecular Biology and Biochemistry methodology is also used to prepare suitable protein samples and assay protein-protein and protein-DNA interactions in vitro.
In eukaryotic nuclei, the genetic material is packaged in chromatin, which, in its “open” state allows the accessibility of gene regulatory factors, while in its most condensed state restricts access of the transcriptional machinery to target genes. The fundamental building blocks of chromatin, the nucleosomes, comprise 147bp of DNA wrapped around an octamer of core histones. These particles further assemble in dense arrays, to form 30nm-fibers and structures of higher order. Chemical modifications of DNA and histones control chromatin remodeling during transcription, mitosis, DNA repair and replication and act individually, sequentially and/or in combination to generate epigenetically heritable gene expression patterns. Distinct structural and functional states of chromatin ranging from “highly active” to “completely silenced" are thus linked with various combinations of histone post-translational modifications, but also with specific nucleosome rearrangements, deposition and/or exchange of histone variants and interactions of chromatin with non-histone regulators. Many protein components of large enzymatic assemblies involved in chromatin remodelling contain specialized protein modules, such as chromo, bromo, TUDOR and PHD domains. It is thought that each one of these domains interacts with a specific chromatin component- post-translationally modified histones- having, ultimately, a distinct effect on chromatin structure and function. However, despite considerable progress in this direction, the functional interaction and the subtle differences between these modules remain poorly understood.
Our research focuses on different aspects of epigenetic regulation and aims at characterizing the structural determinants involved in this process.
- We have been engaged in determining the structures of representative chromatin-associated protein modules of nucleoplasmic and nuclear envelope-associated proteins (e.g., chromodomain, TUDOR domain) and exploring their interactions with chromatin.
- We have constructed a theoretical model, based on state-of-the-art Molecular Dynamics simulations for the interaction of chromatin-related protein modules with multiply modified histones, in collaboration with Kaxiras’ group (EPFL and Harvard University).
- We are involved in modeling the conformational properties and association tendencies of novel experimentally verified (by Georgatos’ group) histone modification patterns peculiar to the mitotic state.
- We are also investigating the binding properties of acidic histone chaperones, such as SET/INHAT, to histones (in collaboration with Papamarcaki group). These acidic proteins recognize and deposit specific histones and their variants onto DNA, but their detailed mechanism of action remains unclear.
Results obtained so far and emerging information from on-going studies on the structure and energetics of chromatin-related complexes are expected to complement existing functional information and address fundamental questions regarding chromatin organization and regulation of its structure in health and disease.
Structure of the Mi-2 chromodomain (left) and of LBR TUDOR domain (right)
Model of a multiply modified histone H3 tail