Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Instituto de Neurociencias de Alicante (Consejo Superior de Investigaciones Científicas- Universidad Miguel Hernández, CSIC-UMH). Campus San Juan, Avd. Ramón y Cajal s/n, 03550 San Juan de Alicante, Spain.
Am J Hum Genet. 2024 Oct 3;111(10):2232-2252. doi: 10.1016/j.ajhg.2024.07.022. Epub 2024 Sep 2.
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.
BAF 染色质重塑因子调节谱系决定，包括颅神经嵴细胞（CNCC）的特化。BAF 亚基的变异导致 Coffin-Siris 综合征（CSS），这是一种先天性疾病，其特征为颅面特征粗糙和智力障碍。大约 50%的 CSS 患者携带相互排斥的 BAF 亚基之一，即 ARID1A/ARID1B 的变异。虽然小鼠神经嵴中的 Arid1a 缺失会导致严重的颅面表型，但 ARID1A 在 CNCC 特化中的作用知之甚少。使用 CSS 患者来源的 ARID1A 诱导多能干细胞来模拟 CNCC 特化，我们发现 ARID1A 杂合不足会损害上皮-间质转化（EMT），这是 CNCC 从神经管分层和迁移所必需的过程。此外，野生型 ARID1A-BAF 调节与 EMT 基因相关的增强子。在杂合子中，ARID1A-BAF 结合这些增强子的能力受损，而结合启动子的能力不受影响。在序列水平上，这些 EMT 增强子包含与 ZIC2 结合的结合基序，并且 ZIC2 在这些位点的结合依赖于 ARID1A。当从 EMT 增强子中排除时，ZIC2 重新定位到神经元增强子，引发异常的神经元基因激活。在小鼠中，Zic2 的缺失会损害 NCC 的分层，而在鸡胚的迁移后神经嵴阶段，ZIC2 在 chick 胚胎中的过表达会引发神经管的异位分层。这些发现揭示了 ARID1A-ZIC2 轴对于 EMT 和 CNCC 分层是必不可少的。
