Project Details
Projekt
Dissecting the role of the chromatin remodeling BAF complex in cell fate determination in human brain organoids
Subject Area
Human Genetics
Developmental Biology
Experimental Models for the Understanding of Nervous System Diseases
Developmental Biology
Experimental Models for the Understanding of Nervous System Diseases
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 563470628
The human brain is among the most complex organs, evolved to perform highly sophisticated cognitive functions. Defects in its development can lead to conditions such as autism, intellectual disability, microcephaly, and other neurological disorders. Comprising billions of cells, the brain harbors over 3000 distinct cell types identified through transcriptional profiling. Modern research utilizing brain development models provides crucial insights into the mechanisms underlying this complexity, tracing the transformation of neural stem cells into specialized functional neurons. However, the epigenetic regulation of transcriptional programs driving these cellular transitions remains poorly understood. This proposal aims to leverage 3D brain organoids derived from induced pluripotent stem cells (iPSCs) to explore the epigenome of early human brain development, with a focus on its role in shaping cell diversity. We will further examine how perturbations in the epigenome influence this diversity. Specifically, we intend to generate brain organoids derived from Coffin-Siris syndrome (CSS) patients. CSS is a rare congenital disorder that disrupts brain development, manifesting in severe symptoms such as autism, microcephaly, and intellectual disability. CSS is primarily associated with mutations in the ARID1B gene, which encodes a protein within the chromatin-remodeling SWI/SNF complex, also known as the BAF (BRG1/BRM-associated factor) complex. Notably, disruptions in this complex often produce characteristic DNA methylation patterns detectable in the blood cells of affected individuals. These epigenomic signatures serve as reliable markers for diagnosing BAFopathies and understanding their pathogenic mechanisms. In this project, we will investigate cell type-specific transcriptomes, epigenomic signatures, and the role of the BAF complex in brain development. Initially, we will generate and characterize CSS patient-derived brain organoids, comparing them to control organoids. We will then analyze alterations in cell diversity and cell type-specific methylation profiles within the CSS organoids. Integrating these findings, we aim to correlate BAF complex defects with observed changes in cell diversity. This work will provide critical insights into how the BAF complex regulates cell fate and plasticity during brain development and elucidate how ARID1B mutations contribute to neurodevelopmental disorders.
DFG Programme
Priority Programmes
