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Séminaire de Ignacio Izeddin

par Webmestre - publié le

« Geometry of the nucleus and gene regulation : a single-molecule and super-resolution microscopy approach »

Ignacio Izeddin
Physico-Chimie Curie (UMR 168)

Gene regulation relies on highly mobile transcription factors (TFs) exploring the nucleoplasm in search of their targets. In the last years, our view of the cell nucleus has evolved from that of an isotropic and homogenous reactor to that of a highly organized yet very dynamic organelle. So far, most studies have focused on how fast TFs diffuse, underestimating the role of nuclear architecture. However important questions remain on how these regulatory factors explore the nuclear environment in search of their DNA or protein targets, and how their exploration strategy affects the kinetics of transcriptional regulation.

Using single-molecule tracking and single-molecule based super-resolution imaging techniques, we have implemented a series of experiments to study the organization of nuclear components, the dynamics of TFs, and the relationship between the two. I will briefly discuss our results on the organization of RNA Polymerase and histones H2B by direct visualization methods at the molecular level [Cisse et al, Science 2013 ; Récamier et al, Nucleus 2014]. Furthermore, I will present our results on the different exploration strategies performed by the proto-oncogene c-Myc and the positive transcription elongation factor-b (P-TEFb) [Izeddin et al, eLife 2014]. Using a single-molecule tracking assay, we found that c-Myc is a global explorer of the nucleus. In contrast, P-TEFb is a local explorer that oversamples its environment. Consequently, each c-Myc molecule is equally available for all nuclear sites while P-TEFb reaches its targets in a position-dependent manner. Our observations are consistent with a model in which the exploration geometry of TFs is restrained by their interactions with nuclear structures and not by exclusion. The geometry-controlled kinetics of TFs target-search illustrates the influence of nuclear architecture on gene regulation, and has strong implications on how proteins react in the nucleus and how their function can be regulated in space and time [Woringer et al, Current Opinion in Chemical Biology, 2014].