Project description
Decoding the regulatory functions of BAF complexes in disease development
Chromatin remodelling BAF complexes in mammals are critical for gene regulation, cellular maintenance and differentiation. Mutations in genes encoding BAF subunits are associated with diseases like cancer and neurodevelopmental disorders (NDDs), while occurrence of specific NDDs depends on the mutant subunit. However, the role of BAF complexes and distinct subunits during brain development are unclear, as are the mechanisms leading to disease phenotypes. The ERC-funded SWitchFate project aims to determine the role of BAF subunits and their mutations in brain development using cerebral organoids, together with epigenomics and proteomics tools. It will also analyse gene regulatory mechanisms altered during brain development, using CRISPR/Cas-based technology. This insight into BAF complexes and disease mechanisms may lead to new treatments for NDDs.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesgeneticsepigenetics
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
55128 Mainz
Germany