Large-scale genomic reorganizations of topological domains (TADs) : insights from the HoxD gene cluster

Orateur : Pierre FABRE (EPFL, Lausanne)

The transcriptional activation of Hoxd genes during limb development involves dynamic interactions with the two Topologically Associating Domains (TADs) flanking the HoxD cluster. The activation of the most posterior Hoxd genes in developing digits is controlled by regulatory elements located in the centromeric TAD (C-DOM) through long-range contacts. To assess the structure-function relationships underlying such interactions, we challenged the robustness of the TAD architecture by using a series of genomic deletions and inversions that impact the integrity of this chromatin domain and that remodel the long-range contacts. We report multi-partite associations between Hoxd genes and up to three enhancers and show that breaking the native chromatin topology leads to the remodelling of TAD structure. Our results reveal that the re-composition of TAD architecture after severe genomic re-arrangements depends on a boundary-selection mechanism that uses CTCF-mediated gating of long-range contacts in combination with genomic distance and sequence specificity. I will also discuss how extremely long-range interactions occur between neuronal genes in telencephalon. Finally I will discuss how we can study the role of dynamic chromatin architecture in the development of the nervous system, and in particular how epigenome remodelling can control neuronal gene function and neural circuit formation.

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