Tuning brain fate through modulation of chromatin remodelling

The mammalian SWI/SNF chromatin remodellers, the BAF complexes, are critical regulators of gene expression by modulating the accessibility of regulatory regions, especially of cell identity genes.

Their importance for cellular maintenance and differentiation is emphasised by the fact that they are frequently associated with disease.

Mutations in genes encoding BAF subunits are found in over 20% of cancers and are causative for neurodevelopmental disorders (NDD). The prevalence for specific NDD with unique clinical features depends on the mutant subunit. The molecular changes leading to the disease phenotypes are largely unresolved.

The functions of BAF complexes and specific subunits during human brain development are also still unclear.

SWItchFate thus aims to systematically identify the role of individual BAF subunits and their mutations in brain development and abnormalities.

To this end, isogenic wild type, mutant and engineered human induced pluripotent stem cell (hiPSC)-derived cerebral organoids will be used in combination with various bulk and single-cell epigenomics and proteomics tools.

SWItchFate will investigate gene regulatory mechanisms altered during brain development with CRISPR/Cas-based loss-of-function screens for all BAF subunits.

Using protein degradation tools targeting specific BAF subunits, SWItchFate will pinpoint vulnerable processes and adaptation mechanisms.

In addition, cell type- and BAF subtype-specific composition, interaction partners and target sites along brain development will be mapped to decipher BAF-dependent gene regulatory networks.

Finally, the molecular changes in BAF mutation-induced NDD that cause the phenotypic changes in patients will be examined and conserved mechanisms across different genotypes will be deciphered using patient-derived hiPSC.

Thus, SWItchFate will decode the regulatory functions of BAF complexes in the context of cell fate decisions in development and disease, paving the way for new therapeutics.