Objective
Chromatin is the physiological template of genetic information controlling the capacity of a cell's genome to store, release, and inherit biological information. The basic unit of chromatin is the nucleosome: a stretch of DNA wrapped around a core of histone proteins. Post-translational modifications of histones have emerged as key in regulating chromatin structure and dynamics and are thought to crucially control genome activity. Whereas correlative studies have begun to establish links between several states of chromatin, various histone modifications, and diverse biological processes, our knowledge of how certain histone modifications exert their biological effects on a molecular level is extremely limited.
One of the principles emerging from our previous studies is that certain histone marks are acting via the recruitment of sequence and modification specific binding proteins (effectors). To get a detailed understanding of the signalling principles within the histone modification/effector protein-signalling network, we propose the reconstitution of complex chromatin systems in vitro. In particular, we intend to analyse the readout and the chromatin effects of three intriguing histone methyl-lysine marks (H3 Lys 9, H3 Lys 27, and H4 Lys 20) that have distinct cellular functions and might work via recruitment of HP1 (heterochromatin protein 1), Pc (Polycomb) and MBT (malignant brain tumour) proteins, respectively. We anticipate that our studies will result in a detailed understanding of fundamental "epigenetic" regulatory pathways that cause inheritable changes in gene function and expression, but do not involve changes in DNA sequence.
We believe that the implications of the proposed research could be far reaching as it is becoming clear that many human disease-states, and in particular cancer have an epigenetic component. This estimation is substantiated by the high promise of experimental drugs targeting histone-modifying enzymes in the treatment of human tumours.
Fields of science
Call for proposal
FP6-2004-MOBILITY-12
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