Abstract
Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B+/− Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of the NANOG and SOX2 networks. In iPSCs, these enhancers are maintained active by ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A- to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout all stages of CNCC formation. This leads to persistent NANOG/SOX2 activity which impairs CNCC formation. Despite showing the typical neural crest signature (TFAP2A/SOX9-positive), ARID1B-haploinsufficient CNCCs are also aberrantly NANOG-positive. These findings suggest a connection between ARID1B mutations, neuroectoderm specification and a pathogenic mechanism for Coffin-Siris syndrome.
Highlights
Cell fate commitment is a complex process that requires timely regulation of developmental genes
In line with findings indicating that the esBAF and the gBAF do not contain ARID1B4–6, we demonstrate that ARID1B mutations do not affect self-renewal and pluripotency of human induced Pluripotent Stem Cells (iPSCs), as pluripotency is conveyed via binding of an ARID1A-containing Brm associated factor (BAF) to pluripotency-associated enhancers of the SOX2 and NANOG networks
Patient-derived iPSCs grew at the same rate as an ARID1B+/+ control line (Control line-1; Fig. 1f)
Summary
Cell fate commitment is a complex process that requires timely regulation of developmental genes. The esBAF predominantly incorporates ARID1A and very rarely ARID1B (relative ARID1B abundance in the esBAF was quantified as ~0 by Ho et al.[6]) One of these studies identified a non-canonical version of BAF (gBAF), which did not contain an ARID subunit and was involved in pluripotency maintenance of mESCs4. Failure to replace ARID1A with ARID1B leads to defective exit from pluripotency and impaired cranial neural crest formation These findings provide evidence for a direct connection between ARID1B mutations and a pathogenic mechanism for ARID1B-associated neurodevelopmental syndromes
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