The activity of BAF complexes ensures forebrain development and brain patterning
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Abstract
Proper brain formation during neurodevelopment relies on tightly regulated gene expression, orchestrated by factors such as the ATP-dependent BAF chromatin remodelling complexes. These complexes are essential for ensuring the timely and accurate activation of trans-criptional programs. Mutations in BAF complex subunits are linked to neurodevelopmental disorders, including Coffin-Siris Syndrome, Nicolaides-Baraitser Syndrome, Autism Spectrum Disorder, and schizophrenia. Despite their significance, the molecular mechanisms by which BAF complex dysfunction disrupts neurodevelopment remain poorly understood.
To address this, human induced pluripotent stem cells (hiPSCs) were differentiated into brain organoids and subjected to temporary treatment with a BAF complex inhibitor targeting the ATPases SMARCA2 and SMARCA4 at different developmental stages. This approach enabled stage-specific and comprehensive analyses of organoid morphology, gene expression (RNA-seq), chromatin accessibility (ATAC-seq, CUT&Tag), protein localization (immunofluorescence), and single-cell dynamics (snRNA- and snATAC-seq) after inhibition of the BAF chromatin remodelling activity.
The results revealed distinct, stage-specific roles of BAF complexes in neurodevelopment, with the most severe effects observed in early neurodevelopmental stages (day 0–12). Early inhibition (day 0–6) resulted in severe disruption of forebrain identity, a shift towards caudal brain regions, disorganized outgrowths, and altered morphology. Inhibition from day 6–12 caused milder defects, including an increase in dorsal telencephalic subtypes, subtle caudalisation, and enlarged neural rosettes. Both phenotypes were linked to irreversible dysregulation of critical signalling pathways, including WNT, YAP, NOTCH, and BMP — key regulators of brain patterning, neural subtype specification, and axonogenesis. This dysregulation was evidenced by changes in gene expression and chromatin landscapes of signalling pathway genes, their targets, and other patterning and cell fate specification genes. Additionally, ARID1B-mutated hiPSC-derived brain organoids displayed altered chromatin accessibility in regions associated with neurodevelopment, providing insights into subunit-specific effects. Notably, the ZIC1 and ZIC4 gene loci were consistently dysregulated following BAF complex inhibition and in the ARID1B-mutated model system, suggesting that these ZIC genes are commonly deregulated upon different BAF complex perturbations.
In conclusion, this study highlights the critical, stage-specific functions of BAF complexes in neurodevelopment. By modulating chromatin accessibility and signalling pathways, BAF complexes regulate brain patterning and neural subtype specification. These findings enhance the understanding of how BAF complex dysfunction contributes to neurodevelopmental disorders and provide a foundation for future therapeutic strategies.