Titre
YY1 mutations disrupt corticogenesis through a cell-type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs
Type
autre
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Auteur(s)
Pereira, Marlene F
Auteure/Auteur
Finazzi, Veronica
Auteure/Auteur
Rizzuti, Ludovico
Auteure/Auteur
Aprile, Davide
Auteure/Auteur
Aiello, Vittorio
Auteure/Auteur
Mollica, Luca
Auteure/Auteur
Riva, Matteo
Auteure/Auteur
Soriani, Chiara
Auteure/Auteur
Dossena, Francesco
Auteure/Auteur
Shyti, Reinald
Auteure/Auteur
Castaldi, Davide
Auteure/Auteur
Tenderini, Erika
Auteure/Auteur
Carminho-Rodrigues, Maria Teresa
Auteure/Auteur
Bally, Julien F
Auteure/Auteur
de Vries, Bert B.A.
Auteure/Auteur
Gabriele, Michele
Auteure/Auteur
Vitriolo, Alessandro
Auteure/Auteur
Testa, Giuseppe
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
Date de publication
2024-02-17
Langue
anglais
Résumé
Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS), a neurodevelopmental disorder featuring intellectual disability and a wide range of systemic manifestations. To dissect the cellular and molecular mechanisms underlying GADEVS, we combined large-scale imaging, single-cell multiomics and gene regulatory network reconstruction in 2D and 3D patient-derived physiopathologically relevant cell lineages. YY1 haploinsufficiency causes a pervasive alteration of cell type specific transcriptional networks, disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons, including cytoarchitectural defects reminiscent of GADEVS clinical features. Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect that grounds the rationale for modulatory interventions. Together, neurodevelopmental trajectories, synaptic formation and neuronal-astrocyte cross talk emerged as salient domains of YY1 dosage-dependent vulnerability. Mechanistically, cell-type resolved reconstruction of gene regulatory networks uncovered the regulatory interplay between YY1, NEUROG2 and ETV5 and its aberrant rewiring in GADEVS. Our findings underscore the reach of advanced in vitro models in capturing developmental antecedents of clinical features and exposing their underlying mechanisms to guide the search for targeted interventions.
PID Serval
serval:BIB_C8D831F450E5
PMID
Date de création
2024-11-04T16:36:33.018Z
Date de création dans IRIS
2025-05-21T01:58:18Z