YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs

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.

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Publication Details

Journal
Molecular Psychiatry
Published
2025-02-22
DOI
https://doi.org/10.1038/s41380-025-02929-x
Citations
6
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
4.84

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article

YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs

Davide Aprile, Erika Tenderini, Michele Gabriele, Maria Teresa Carminho‐Rodrigues et al.
6 citations
Molecular Psychiatry
Single-cell and spatial transcriptomics
4.84
article

YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs

Davide Aprile, Erika Tenderini, Michele Gabriele, Maria Teresa Carminho‐Rodrigues, Davide Castaldi, Alessandro Vitriolo, Francesco Dossena, Chiara Soriani, Reinald Shyti, Bert B.A. de Vries, Ludovico Rizzuti, Marlene F. Pereira, Julien F. Bally, Giuseppe Testa, Veronica Finazzi, Vittorio Aiello, Luca Mollica, Matteo Marco Riva
article en
6 citations

Abstract

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.

Molecular PsychiatryVol. 30(8)
Broad Institute (US), University of Geneva (CH), Radboud University Nijmegen (NL), University of Milan (IT), University Hospital of Geneva (CH), Human Technopole (IT), Allen Institute (US), Ospedale San Giuseppe (IT), European Institute of Oncology (IT), Massachusetts Institute of Technology (US), University of Lausanne (CH)
American-Italian Cancer Foundation, E-Rare, Associazione Italiana per la Ricerca sul Cancro, National Institutes of Health, Horizon 2020 Framework Programme, H2020 Marie Skłodowska-Curie Actions
Openalex Percentile: Top 5%
Single-cell and spatial transcriptomics
4.84
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