Seminars – Structural organisation of human replication timing domains

EVENT : C3BI Seminars

Structural organisation of human replication timing domains

Main speaker : Benjamin Audit, from Chromatin and Genome Group – Ecole Normale Supérieure de Lyon Date : 20/10/2016 at 02:00 pm Location : Retrovirus room – LWOFF (22) ,Institut Pasteur, Paris

Structural organisation of human replication timing domains

Understanding how the DNA double helix is spatially and dynamically organized in the nucleus of eukaryotic cells and how this affects genome functions is one of the main challenges of cell biology. In this seminar, I will illustrate that when combining concepts and methodologies coming from physics with wavelet-based multi-scale signal processing, we are able to extract original information about the structure/function relationship in the nucleus. I will review some recent analyses of genome-wide epigenetic modification data, mean replication timing (MRT) profiles and chromosome conformation (HiC) data that have established some link between the spatio-temporal replication program, gene expression and chromatin structural domains. This provides an analysis framework for the understanding of the epigenetically regulated global chromatin reorganization that underlies the loss of pluripotency during cell differentiation in human. The proposed view reconciles the dichotomic picture of early transcriptionally active and late heterochromatin constant timing regions that replicate by multiple rather synchronous origins in separated nuclear compartments of open and closed chromatins, with the model proposed by our group where U-shaped MRT domains are bordered by ‘‘master’’ replication origins from which a replication wave initiates and propagates toward the domain centre via a cascade of origin firing. I will finally discuss a unified framework based on equilibrium globule models where early euchromatin regions behave as a simple 3D equilibrium globule while, specifically in differentiated cell lines, chromatin folding in heterochromatin regions is compatible with a transition to 2D equilibrium dynamics associated with the nuclear lamina. This transition corresponds to a progressive segregation from 3D dynamics at the nucleus centre of early replicating regions to 2D dynamics confined at the nuclear envelop of late replicating regions. These results shed a new light on replication foci formation and dynamics in human, depending on the cells’ differentiation status.

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