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Packaging of DNA into chromatin enables different ways of functionally compartmentalizing the same genome. The two major functional compartments are, actively transcribed regions called euchromatin and, strongly repressed regions called heterochromatin. Euchromatin is characterized by constant dynamic changes in the structures, positions and composition of nucleosomes, which enable regulated access to the transcription machinery. In contrast heterochromatin is characterized by highly ordered nucleosomes, which form condensed structures and inhibit DNA access. The functional compartments undergo dramatic rearrangements during differentiation and development as different gene expression patterns are established to define cell identity. ATP-dependent chromatin remodeling machines, histone modifying enzymes and histone binding proteins are the workhorses that maintain these functional compartments and also cause their rearrangement. The last two decades have seen an explosion in the identification of these types of chromatin regulators. Yet, fundamental mechanistic questions remain unanswered.
1. How do chromatin-remodeling machines alter chromatin and what are the structural consequences?
2. How do histone-modifying enzymes and histone readers collaborate on chromatin?
3. How is diversity achieved from homologous chromatin regulators?
We are addressing these questions by (i) using in depth biophysical characterization to unravel the core mechanistic capabilities of chromatin regulators and by (ii) reconstituting and studying the process of heterochromatin assembly in vitro. We have had the fortune of being confronted by data that has challenged our favored hypotheses and resulted in unanticipated discoveries. We have also learnt that our ability to frame and address mechanistic questions is linked to the scope of the biophysical approaches that we use. Overall our group enjoys tackling intellectually challenging mechanistic mysteries through rigorous quantitative analysis.