The role of histone-methyltransferase Setd1b in brain development

Precise control of gene expression is essential for brain development and cognitive function. As a starting point this project investigates how the histone methyltransferase SETD1B, an enzyme that modifies chromatin to activate transcription, regulates neuronal identity and how its dysfunction contributes to intellectual developmental disorders (IDDs). Mutations in SETD1B are known to cause IDDs, yet the underlying mechanisms remain unclear. Using human induced pluripotent stem cell (iPSC)-derived cortical organoids carrying patient-specific SETD1B mutations, we will define how altered histone methylation affects neuronal differentiation, migration, and network formation. Building on our previous findings that SETD1B controls neuron-specific gene expression, we further explore how long non-coding RNAs (lncRNAs) guide chromatin-modifying enzymes, such as SETD1B to the correct genomic loci. By combining single-cell transcriptomics, chromatin profiling, and functional assays in iPSC derived neural cells and organoids, this study aims to uncover how the interaction between epigenetic regulators and ncRNAs shapes neuronal gene programs during cortical development. Understanding this regulatory mechanism will not only help clarify the epigenetic basis of IDDs but may also open new therapeutic avenues for neurodevelopmental and neurodegenerative disorders.