Speaker
Description
"Weaver syndrome (WVS) is a multisystem disorder, characterized by pre- and post-natal overgrowth and intellectual disability. WVS genetic cause was identified in heterozygous mutations in Polycomb repressive complex 2 (PRC2). This complex catalyzes the tri-methylation of Lysine 27 on histone 3 (H3K27me3), promoting transcriptional repression during corticogenesis. Our knowledge about the impact of PRC2 misfunction in corticogenesis and the impact of the WVS heterozygous mutations on the landscape of H3K27me3 and the resulting transcriptomic changes are incomplete and based on mouse data. To better understand the molecular mechanisms underlying WVS, we conducted transcriptomic and epigenomic analyses of patient-derived cortical brain organoids (CBOs) cultured for up to 250 days in vitro.
Our multi-omic approach integrated bulk and single-cell RNA sequencing, EZH2 and H3K27me3 genomic distribution mapping and DNA methylation profiling. These analyses revealed disruptions in neuronal maturation and migration from day 25 to 250 of differentiation. We observed temporally regulated gene expression defects and asynchronous cell type emergence in WVS, particularly affecting indirect neurogenesis. By identifying specific transcription factors responsible for cell-type dysregulation, we highlighted defects in cell fate commitment and migration. This finding is consistent with clinical data from WVS patients, whose MRI profiles show altered cortical development associated with defects in later stages of neuronal migration. Moreover, we identified AJAP1 as upregulated in WVS CBOs at day 25. AJAP1 cooperates with multiple proteins to organize the adherens junctions belt, potentially determining radial glial cell fate. We developed a CRISPRa system to upregulate AJAP1 in control CBOs highlighting its relationship with EZH2 in neuronal migration. This study provides the first comprehensive molecular characterization of PRC2's role in human cortical development and its involvement in neuronal migration, addressing a significant knowledge gap. Our findings advance the understanding of WVS pathogenesis and establish new resources for investigating neurodevelopmental disorders."
| Author(s) | Martina Pezzali*, Sebastiano Trattaro*, Alessandro Vitriolo*, Sara Sebastiani, Claudio Maderna, Lorenza Culotta, Filippo Mirabella, Michele Gabriele, Filippo Prazzoli, Cristina Cheroni, Pietro Lo Riso, Erika Tenderini, Sanaa Choufani, Rosanna Weksberg, Romano Tenconi, William Gibson, Alejandro Lopez Tobon, Giuseppe Testa. |
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| Affiliation(s) | Human Technopole, Human Technopole, Human Technopole, European Institute of Oncology, Human Technopole, Human Technopole, Human Technopole, European Institute of Oncology, University of Milan, Human Technopole, European Institute of Oncology, European Institute of Oncology, The Hospital for Sick Children, The Hospital for Sick Children, University of Padova, BC Children's Hospital, European Institute of Oncology, Human Technopole. |
