Thèse Régulation des Gènes Associés à la Mémoire Long Terme par les Enhancers H/F - Doctorat.Gouv.Fr

Établissement : Université de Montpellier
École doctorale : Sciences Chimiques et Biologiques pour la Santé
Laboratoire de recherche : CBS - Centre de Biologie Structurale
Direction de la thèse : Marcelo NOLLMANN-MARTINEZ ORCID 0000000333392349
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-05-11T23:59:59

Chez de nombreux organismes, la formation de la mémoire à long terme (MLT) nécessite une transcription de novo dans les neurones impliqués dans l'encodage de la mémoire. L'hypothèse que nous testerons est que la régulation de ce programme transcriptionnel implique des séquences enhancers recrutant le facteur de transcription CREB. Nous proposons d'aborder cette question en caractérisant l'impact de la délétion d'enhancers candidats et de la déplétion de facteurs chromatiniens spécifiques sur la transcription des gènes de la mémoire et sur leur structure 3D de la chromatine, en utilisant la technique de smRNA-FISH séquentielle et la méthode Hi-M.

Enhancers can be described as autonomous, modular, orientation-independent DNA cis-regulatory sequences that regulate transcription in space and time. This regulation involves the recruitment of sequence-specific transcription factors to enhancer sites, as well as communication of the enhancer with the promoter to change its activation state.
The mechanism linking neuronal activity to gene expression changes during LTM formation is conserved from Drosophila to mice, and involves the integration of synaptic signals (e.g. neurotransmitters) by G-protein-coupled receptors that trigger an intracellular signalling cascade resulting in the phosphorylation of a key transcription factor: the cyclic AMP response element-binding protein (CREB in vertebrates, CrebB in Drosophila). In Drosophila, this cascade occurs in the Mushroom Body, a brain structure that is known to be required for the formation of LTMs. Critically, phosphorylated CREB recruits co-factors to DNA, including the conserved histone acetyltransferase CREB-binding protein (CBP), to activate transcription of multiple target genes in specific MB cell types by binding to specific CREB regulatory elements. Yet, how CREB enhancers contribute to changes in 3D chromatin organization and to transcriptional regulation of CREB target genes remains largely unknown.

Recent studies already uncovered essential long-term memory genes, encoding transcription factors including CREB (Jones et al. Nat Commun 2025). Using fly models allowing controlled deletion of candidate enhancers or perturbation of specific factors, we aim to characterize their impact on the transcription of LTM-associated genes using sequential smRNA-FISH on whole-mount dissected fly brains. In addition, by using HiM, we will be able to visualize whether these perturbations impact the 3D organization of chromatin around CREB target genes, particularly the proximities between CREB promoters and CREB enhancers.

The host lab recently pioneered the development of Hi-M, an imaging-based technology that enables the direct detection of transcription and the simultaneous visualization of chromosome organization in single cells within tissues (Cardozo et al. Mol Cell 2019; Espinola et al Nat Genetics 2021). Notably, Hi-M intrinsically conserves spatial information, thus allowing for the reconstruction of the 3D chromatin organization of different cell-types within tissues in specific positions, and uplifts many of the limitations of sequencing-methods highlighted above. Recently, we have been able to adapt HiM to reconstruct chromatin organization in the fly brain, to detect differential chromatin configurations between distinct mushroom body neuron types.

Written and spoken English. Experience with lab work, particularly molecular biology, fly genetics, fluorescence imaging, bioinformatics analysis.