Epigenetic regulation in human cortical organoid models of Weaver syndrome

• Applicants: Professorin Dr. Mareike Albert; Dr. Maximilian Krause, since 11/2025
• Subject Area: Developmental Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560346098

The neocortex controls higher cognitive functions. Changes in cortical neuron number, brain size, cortical folding or brain structure may manifest in neurodevelopmental disorders. Among the causes of neurodevelopmental disorders are mutations in the epigenetic machinery, such as the enzymes that mediate histone posttranslational modifications. However, for many neurodevelopmental disorders, the altered cortical development, critical developmental time window and molecular mechanisms have not been elucidated. Here, we propose to dissect the functional role of epigenetic regulation in Weaver syndrome, which represents a rare overgrowth syndrome and neurodevelopmental disorder caused by mutations in the Polycomb group histone methyltransferase EZH2. Weaver syndrome patients often display macrocephaly, referring to a critical increase in brain size, structural brain abnormalities and intellectual disability. We have established isogenic induced pluripotent stem cell (iPSC) lines carrying Weaver syndrome patient mutations. The iPSC lines can be induced to generate human cortical organoids. These new disease models allow us 1) to characterize neural progenitor cell proliferation and neurogenesis, 2) to decipher the epigenetic mechanisms of neural gene regulation, 3) to explore the reversibility of epigenetic and phenotypic changes, and 4) to analyse neuronal maturation and activity. Overall, this project combines human disease models and epigenetic analysis to elucidate the cellular and molecular mechanisms underlying the neurodevelopmental changes in Weaver syndrome, with the goal to provide a framework for exploring epigenetic modulators in the context of neurodevelopment.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Andreas Dahl, until 11/2025