Modeling chromatin fibre folding for human embryonic stem cells and cancer cells
Seminar Room 1, Newton Institute
AbstractAll diverse cell types in an organism essentially have an identical genome. Generation of tissue specific cells is through an epigenomic process in which progressive alterations in the chromatin state generates lineage committed cells from pluripotent embryonic stem cells. Ultimately, establishment of terminally differentiated cells results in a stable chromatin state. Chromatin modification can be studied by chromatin immunoprecipitation (ChIP) that identifies regions that are over-represented as transcriptionally active sequences. In this talk we describe chromatin-state maps for pluripotent, cancer and lineagecommitted cells using three-dimensional modelling of fibre conformation. The model takes into account of the local structure of chromatin organised into euchromatin (open chromatin), permissive for gene activation, and heterochromatin (closed chromatin), transcriptionally silenced. Open chromatin is assumed to be modelled by a linker DNA while the closed chromatin by means of a solenoid structure in which DNA winds onto six nucleosome spools per turn with two left-handed superhelical turns around an histone octamer. The model represents a single gyre of a solenoid by means of a torus knot that winds around a torus once in the longitudinal direction and twelve in the meridian direction. Closed and open chromatin is then connected by means of piecewise polynomial transformations based on cubic Hermite spline functions. As reprogramming process is associated both with pluripotency and the neoplastic process, our analyses potentially identify cancer-related epigenetic abnormalities. Chromatin fibre conformation are compared in terms of geometric quantities such as curvature and torsion localization, and relative rates, in relation to filament compaction and packing efficiency. This study provides information on relationships between geometry and the transcriptional regulation in stem cells and cancer cells contributing to pluripotency and self-renewal.
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