The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of individuals with CSS harbor variants in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS-patient-derived ARID1A+/− induced pluripotent stem cells to model CNCC specification, we discovered that ARID1A-haploinsufficiency impairs epithelial-to-mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at post-migratory neural crest stages elicits ectopic delamination from the neural tube. These findings reveal an essential ARID1A-ZIC2 axis essential for EMT and CNCC delamination.

中文翻译：

---

ARID1A-BAF 协调颅神经嵴规范中上皮到间充质转变的 ZIC2 基因组占有率


BAF 染色质重塑剂调节谱系定型，包括颅神经嵴细胞 （CNCC） 规格。BAF 亚基的变异会导致 Coffin-Siris 综合征 （CSS），这是一种以粗糙的颅面特征和智力障碍为特征的先天性疾病。大约 50% 的 CSS 个体在互斥的 BAF 亚基之一 ARID1A/ARID1B 中携带变异。虽然小鼠神经嵴中的 Arid1a 缺失会导致严重的颅面表型，但对 ARID1A 在 CNCC 规范中的作用知之甚少。使用 CSS 患者来源的 ARID1A+/- 诱导的多能干细胞对 CNCC 规范进行建模，我们发现 ARID1A 单倍体不足损害上皮到间充质转化 （EMT），这是 CNCC 分层和从神经管迁移所必需的过程。此外，野生型 ARID1A-BAF 调节与 EMT 基因相关的增强子。杂合子中 ARID1A-BAF 与这些增强子的结合受损，而启动子的结合不受影响。在序列水平上，这些 EMT 增强子包含 ZIC2 的结合基序，并且这些位点的 ZIC2 结合是 ARID1A 依赖性的。当从 EMT 增强子中排除时，ZIC2 重新定位到神经元增强子，触发异常的神经元基因激活。在小鼠中，Zic2 的缺失会损害 NCC 分层，而 ZIC2 在迁嵐后神经嵴阶段的鸡胚胎中过表达会引起神经管的异位分层。这些发现揭示了 EMT 和 CNCC 分层所必需的 ARID1A-ZIC2 轴。