The BAF complex, a key chromatin remodeler, regulates transcription, replication, and repair in a
cell-type-specific and spatiotemporally controlled manner. Mutations in core BAF subunits (SMARCC1,
SMARCA4, SMARCB1) cause BAFopathies, a group of neurodevelopmental disorders. While known
that SMARCC1 loss disrupts neural stem cell regulation, it remains unclear whether similar
dysregulation occurs in other BAF subunits, leading to abnormal neural development. To address this,
CHOPIN will use human 3D choroid plexus organoids to map cell-type-specific transcriptional
regulation and cerebrospinal fluid (CSF) diversity of BAF subunits across development. The choroid
plexus is a relevant research model since CSF influences neural stem cells. Building on this
foundation, we will examine noncoding regulatory mechanisms, focusing on developing and
perturbing gene regulatory networks to elucidate how BAFopathy variants influence the regulatory
network of neural stem cells in the choroid plexus. Additionally, we will explore whether EZH2
inhibition via tazemetostat—exploiting synthetic lethality between EZH2 and SMARCB1—can restore
BAFopathy-associated defects, hypothesizing a shared vulnerability across early subunits. Overall,
this project will deepen our understanding of the role of the BAF-complex in the choroid plexus
during neurodevelopment and disease and may contribute to the development of novel therapeutic
strategies for BAFopathies.